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<div class='row cover-caption'> <div class='small-12 columns'> <h3 class='issue'> Issue published January 16, 2025 <span class='browse'> <a id="issue#show_previous_issue" href="/135/1">Previous issue</a> | <a id="issue#show_next_issue" href="/135/3">Next issue</a> </span> </h3> </div> </div> <div class='row'> <div class='large-3 medium-4 columns'> <img class="issue-cover" src="//dm5migu4zj3pb.cloudfront.net/volumes/135/2/135-2-cover.jpg" /> </div> <div class='large-9 medium-8 columns'> <ul class='no-bullet'> <li> Volume 135, Issue 2 </li> </ul> <h5>Go to section:</h5> <ul class='no-bullet'> <li> <a href='#viewpoint'> Viewpoint </a> </li> <li> <a href='#review'> Reviews </a> </li> <li> <a href='#commentary'> Commentaries </a> </li> <li> <a href='#research_letter'> Research Letter </a> </li> <li> <a href='#research_article'> Research Articles </a> </li> <li> <a href='#corrigendum'> Corrigendum </a> </li> </ul> </div> </div> <div class='row'> <div class='small-12 columns'> <h4 class='cover-story-headline'> On the cover: Tristetraprolin regulates phenotypic plasticity of prostate cancer </h4> <div><p><a href="/articles/view/175680">Morel et al.</a> report that tristetraprolin loss or its reduced expression activates NF-κB–induced phenotypic plasticity and primes the transition to lethal prostate cancer, which can be mitigated by treatment with the NF-κB inhibitor, dimethylaminoparthenolide. The cover image shows reactive stroma (blue) in the prostate of a mouse with prostate-specific <i>Pten</i> and <i>Zfp36</i> loss (Masson’s trichrome staining). Image credit: Katherine L. Morel.</p> </div> </div> </div> <a class='in-page' name='viewpoint'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel0' name='viewpoint'> <strong></strong> <span class='toggle-icon'></span> Viewpoint </a> <div class='content active' id='panel0'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/189625">MicroRNAs: where brilliance, perseverance, and ambition converged</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/189625">Rares Drula, George A. Calin</a> <a class='hide-for-small show-more' data-reveal-id='article45750-more' href='#'> <div class='article-authors'> Rares Drula, George A. Calin </div> </a> <span class='article-published-at'> Published December 10, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e189625. <a href="https://doi.org/10.1172/JCI189625">https://doi.org/10.1172/JCI189625</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/189625">Text</a> | <a href="/articles/view/189625/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI189625' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/189625/figure/1' ref='group' title='microRNA research: from sequences to hallmarks. (A) The regulatory relationship between lin-4 and lin-14, as defined by the discoveries of Ambros and Ruvkun, highlighting the seven complementary binding sites of lin-4 on the 3′ UTR of lin-14. (B) The evolutionary conservation of let-7 sequences is displayed across key model organisms, including Caenorhabditis elegans, Drosophila melanogaster, mice (Mus musculus), and humans (Homo sapiens). (C) MicroRNAs at the intersection of cancer hallmarks, highlighting their involvement in processes such as immune evasion, angiogenesis, metastasis, and cellular proliferation. While significant progress has been made in understanding their roles, many aspects remain undefined, emphasizing the need for further research into their complex contributions to tumor biology and cancer progression.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/189000/189625/small/JCI189625.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45750-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/189625">MicroRNAs: where brilliance, perseverance, and ambition converged</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/189625">Text</a></li> <li><a class="button tiny" href="/articles/view/189625/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p></p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Rares Drula, George A. Calin</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='review'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel1' name='review'> <strong></strong> <span class='toggle-icon'></span> Reviews </a> <div class='content active' id='panel1'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/185218">T cells in cardiac health and disease</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185218">Pilar Martín, Francisco Sánchez-Madrid</a> <a class='hide-for-small show-more' data-reveal-id='article45696-more' href='#'> <div class='article-authors'> Pilar Martín, Francisco Sánchez-Madrid </div> </a> <span class='article-published-at'> Published January 16, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e185218. <a href="https://doi.org/10.1172/JCI185218">https://doi.org/10.1172/JCI185218</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185218">Text</a> | <a href="/articles/view/185218/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI185218' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/185218/figure/1' ref='group' title='The role of CD69 in various cardiovascular pathologies. (A) oxLDL binding to the CD69 receptor regulates NR4A expression in T cells, which has been shown to promote Treg differentiation. In mice, CD69 deficiency has been linked to altered NR4A1 expression, Treg–Th17 cell imbalance, and exacerbation of atherosclerosis. oxLDL/CD69 signaling also regulates PD-1 expression in CD4+ T cells, which is known to regulate vascular changes in the inflamed aorta. (B) The CD69 receptor’s interaction with oxLDL, Gal-1, and S100A8/S100A9 regulates the FOXP3/RORγt pathway to promote Treg differentiation. In models of myocarditis and dilated cardiomyopathy, CD69–/– hearts have altered Treg–Th17 cell immune cell infiltration and altered RORγt/Foxp3 signaling. (C) In models of myocardial ischemia, CD69 deficiency increases infarct size. CD69 is linked to activation of the aryl hydrocarbon receptor (AhR) and increased CD39 transcription, which promotes Treg control of γδ T cell activity.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/185000/185218/small/JCI185218.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45696-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185218">T cells in cardiac health and disease</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185218">Text</a></li> <li><a class="button tiny" href="/articles/view/185218/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, with inflammation playing a pivotal role in its pathogenesis. T lymphocytes are crucial components of the adaptive immune system that have emerged as key mediators in both cardiac health and the development and progression of CVD. This Review explores the diverse roles of T cell subsets, including Th1, Th17, γδ T cells, and Tregs, in myocardial inflammatory processes such as autoimmune myocarditis and myocardial infarction. We discuss the contribution of T cells to myocardial injury and remodeling, with emphasis on specific immune receptors, e.g., CD69, that have a critical role in regulating immune tolerance and maintaining the balance between T cell subsets in the heart. Additionally, we offer a perspective on recent advances in T cell–targeted therapies and their potential to modulate immune responses and improve clinical outcomes in patients with CVD and in heart transplant recipients. Understanding the intricate interplay between T cells and cardiovascular pathology is essential for developing novel immunotherapeutic strategies against CVD.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Pilar Martín, Francisco Sánchez-Madrid</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/185785">Recent clinical and mechanistic insights into vitiligo offer new treatment options for cell-specific autoimmunity</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185785">Khaled Ezzedine, … , Todd F. Pearson, John E. Harris</a> <a class='hide-for-small show-more' data-reveal-id='article45701-more' href='#'> <div class='article-authors'> Khaled Ezzedine, … , Todd F. Pearson, John E. Harris </div> </a> <span class='article-published-at'> Published January 16, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e185785. <a href="https://doi.org/10.1172/JCI185785">https://doi.org/10.1172/JCI185785</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185785">Text</a> | <a href="/articles/view/185785/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI185785' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/185785/figure/1' ref='group' title='Clinical presentations of vitiligo. (A and B) Individuals with nonsegmental vitiligo, displaying characteristic symmetrical lesions on the body. Note normal body hair pigmentation in A. (C and D) Segmental vitiligo, with asymmetric lesions limited by the midline. Note depigmented lesional hairs in C. (E) Mixed vitiligo, characterized by segmental lesions that stop at the midline on the left anterior trunk as well as symmetric nonsegmental lesions on the hands. Photos are shown with patient consent.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/185000/185785/small/JCI185785.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45701-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185785">Recent clinical and mechanistic insights into vitiligo offer new treatment options for cell-specific autoimmunity</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185785">Text</a></li> <li><a class="button tiny" href="/articles/view/185785/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Vitiligo is an autoimmune disease that has been recognized, stigmatized, and treated for millennia. Recent translational research has revealed key mechanisms of disease, including cellular stress, innate immune activation, T cell–mediated elimination of melanocytes from the skin resulting in clinically apparent white spots, as well as stem cell regeneration that reverses established lesions. Many of these pathways have been targeted therapeutically, leading to the first FDA-approved medication to reverse the disease, with many more in clinical trials. Despite these impressive advances, many questions remain, which will be answered through integration of additional basic, translational, and clinical research studies. This vitiligo revolution has led to great excitement for individuals with vitiligo, those who know them, and the dermatologists who care for their patients. But just as importantly, these advances have great potential to shed light on autoimmune diseases that are more difficult to study, possibly leading to treatment advances that could not be achieved otherwise.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Khaled Ezzedine, Rim Tannous, Todd F. Pearson, John E. Harris</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='commentary'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel2' name='commentary'> <strong></strong> <span class='toggle-icon'></span> Commentaries </a> <div class='content active' id='panel2'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/187567">A new twist on superantigen-activated autoimmune disease</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/187567">Andrew L. Mason, … , Doaa Waly, Mohammed S. Osman</a> <a class='hide-for-small show-more' data-reveal-id='article45679-more' href='#'> <div class='article-authors'> Andrew L. Mason, … , Doaa Waly, Mohammed S. Osman </div> </a> <span class='article-published-at'> Published January 16, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e187567. <a href="https://doi.org/10.1172/JCI187567">https://doi.org/10.1172/JCI187567</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/187567">Text</a> | <a href="/articles/view/187567/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI187567' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/187567/figure/1' ref='group' title='The SKG mouse model of RA supports an endogenous and/or exogenous MMTV Sag-driven autoimmune response. T cells develop in the thymus and progress through positive and negative selection. (A) In WT BALB/c mice, thymocytes that react with endogenous MMTV encoded Sags are actively deleted. (B) In contrast, the SKG mouse model with a hypomorphic ZAP-70 protein results in positively selected Sag-reactive and autoimmune T cells that have impaired signaling downstream of the TCR/peptide-MHC complex. (C) Sags may promote arthritis via two potential models: (i) In the periphery, endogenously encoded Mtv Sag activates cognate TCR-Vβ subsets, and these autoimmune naive arthritogenic CD4+ T cells home to SKG joints to initiate disease; or (ii) exogenous MMTV arises as a result of resurrected endogenous retroelements in the setting of immunodeficiency and replicates in proliferating cognate TCR-Vβ T cells activated by viral Sags. These lymphocytes home to infect joints, where autoimmune and CD8+ cytotoxic T cell responses to MMTV instigate arthritis. pMHC, peptide MHC.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/187000/187567/small/JCI187567.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45679-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/187567">A new twist on superantigen-activated autoimmune disease</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/187567">Text</a></li> <li><a class="button tiny" href="/articles/view/187567/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Superantigen-induced (Sag-induced) autoimmunity has been proposed as a mechanism for many human disorders, without a clear understanding of the potential triggers. In this issue of the JCI, McCarthy and colleagues used the SKG mouse model of rheumatoid arthritis to characterize the role of Sag activity in inflammatory arthritis by profiling arthritogenic naive CD4+ T cells. Within the diseased joints, they found a marked enrichment of T cell receptor–variable β (TCR-Vβ) subsets that were reactive to the endogenously encoded mouse mammary tumor virus (MMTV) Sag. Arthritis was improved using reverse transcriptase inhibitors. Moreover, depletion of MMTV Sag-activated TCR-Vβ subsets affected the ability of transferred activated CD4+ T cells to induce disease in mice with severe combined immunodeficiency (SCID). Further virological studies should determine whether endogenous or exogenous MMTV is necessary or sufficient to trigger inflammatory arthritis in the SKG model.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Andrew L. Mason, Doaa Waly, Mohammed S. Osman</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/188368">No bones about it: regulatory T cells promote fracture healing</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/188368">Jason W. Griffith, Andrew D. Luster</a> <a class='hide-for-small show-more' data-reveal-id='article45688-more' href='#'> <div class='article-authors'> Jason W. Griffith, Andrew D. Luster </div> </a> <span class='article-published-at'> Published January 16, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e188368. <a href="https://doi.org/10.1172/JCI188368">https://doi.org/10.1172/JCI188368</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/188368">Text</a> | <a href="/articles/view/188368/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI188368' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/188368/figure/1' ref='group' title='Tregs at the site of bone injury contribute to bone repair via the CCL1/CCR8 axis. Bone fracture induces CCL1 production from bone marrow macrophages, resulting in the accumulation of CCR8+ Tregs at the injury site. CCL1/CCR8 signaling in Tregs induces the expression of the transcription factor BATF, which in turn induces PGRN secretion. PGRN promotes skeletal stem cell differentiation, osteogenic function, and new bone formation.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/188000/188368/small/JCI188368.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45688-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/188368">No bones about it: regulatory T cells promote fracture healing</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/188368">Text</a></li> <li><a class="button tiny" href="/articles/view/188368/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Regulatory T cells (Tregs) are increasingly being recognized for their role in promoting tissue repair. In this issue of the JCI, Chen et al. found that Tregs at the site of bone injury contribute to bone repair. The CCL1/CCR8 chemokine system promoted the accumulation of Tregs at the site of bone injury, where Tregs supported skeletal stem cell (SSC) accumulation and osteogenic differentiation. CCL1 increased the transcription factor basic leucine zipper ATF-like transcription factor (BATF) in CCR8+ Tregs, which induced the secretion of progranulin that promoted SSC osteogenic function and new bone formation. This study highlights the ever-expanding role of Tregs in tissue repair by demonstrating their ability to expand stem cells at a site of injury.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Jason W. Griffith, Andrew D. Luster</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/188538">Elucidating the role of autoreactive T cells and B cells in autoimmune hepatitis</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/188538">Yoshiaki Yasumizu, David A. Hafler</a> <a class='hide-for-small show-more' data-reveal-id='article45683-more' href='#'> <div class='article-authors'> Yoshiaki Yasumizu, David A. Hafler </div> </a> <span class='article-published-at'> Published January 16, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e188538. <a href="https://doi.org/10.1172/JCI188538">https://doi.org/10.1172/JCI188538</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/188538">Text</a> | <a href="/articles/view/188538/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI188538' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/188538/figure/1' ref='group' title='B cells orchestrate autoreactive CD4+ T cells in AIH. SepSecS-specific B cells present antigens to autoreactive CD4+ T cells via MHC class II molecules. Liver-infiltrating SepSecS-specific CD4+ T cells secrete IL-10, IL-4, and IFN-γ. The pathways may have a central role in the pathogenesis of AIH by driving the generation of pathogenic T cells that contribute to liver tissue damage.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/188000/188538/small/JCI188538.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45683-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/188538">Elucidating the role of autoreactive T cells and B cells in autoimmune hepatitis</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/188538">Text</a></li> <li><a class="button tiny" href="/articles/view/188538/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>How are autoreactive T cells induced and regulated in patients with autoimmune disease? This question lies at the core of understanding autoimmune disease pathologies, yet it has remained elusive due to host variability and the complexity of the immune system. In this issue of the JCI, Kramer and colleagues used autoimmune hepatitis (AIH) as a model to explore the maintenance of autoreactive CD4+ T cells specific to O-phosphoseryl-tRNA:selenocysteine tRNA synthase (SepSecS). The findings provide insight into the interaction between T cells and B cells in AIH pathogenesis that may reflect a shared mechanism among other autoimmune diseases.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yoshiaki Yasumizu, David A. Hafler</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='research_letter'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel3' name='research_letter'> <strong></strong> <span class='toggle-icon'></span> Research Letter </a> <div class='content active' id='panel3'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/180670">Single-nuclei transcriptomics reveals TBX5-dependent targets in a patient with Holt-Oram syndrome</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/180670">Jeffrey D. Steimle, … , Xiao Li, James F. Martin</a> <a class='hide-for-small show-more' data-reveal-id='article45689-more' href='#'> <div class='article-authors'> Jeffrey D. Steimle, … , Xiao Li, James F. Martin </div> </a> <span class='article-published-at'> Published November 14, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e180670. <a href="https://doi.org/10.1172/JCI180670">https://doi.org/10.1172/JCI180670</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/180670">Text</a> | <a href="/articles/view/180670/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI180670' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/180670/figure/1' ref='group' title='Identification of TBX5-dependent targets at single-cell resolution. (A) TBX5 gene (top) and protein (bottom) with domains labeled. Patient mutation c.254C>G (p.P85R) is indicated by an arrowhead. (B) Anti-HA and wheatgerm agglutinin (WGA) immunofluorescence staining of FaDu cells transfected with HA-TBX5-WT or HA-TBX5-P85R (original magnification, ×40). Ratiometric quantification of nucleus-to-cytoplasm HA signal by box plot (n = 6). P value was determined by Welch’s 2-sample t test. (C) Volcano plot showing the distribution of differentially expressed genes (FDR <0.05 and |log2fold change| >0.25) comparing HOS and control cardiomyocytes. (D) OR by Fisher’s exact test comparing the overlap of down- and upregulated genes identified in C and in published TBX5-KO iPSC-derived cardiomyocytes (2). (E) OR by Fisher’s exact test comparing the overlap of down- and upregulated genes identified in C and published TBX5 ChIP-Seq from iPSC-derived cardiomyocytes (Supplemental Ref 14). (F) Gene ontology (GO) term analysis of TBX5-dependent genes associated with TBX5 ChIP-Seq not previously reported in cardiomyocyte-derived iPSCs or mouse tissue.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/180000/180670/small/JCI180670.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45689-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/180670">Single-nuclei transcriptomics reveals TBX5-dependent targets in a patient with Holt-Oram syndrome</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/180670">Text</a></li> <li><a class="button tiny" href="/articles/view/180670/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p></p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Jeffrey D. Steimle, Yi Zhao, Fansen Meng, Mikaela E. Taylor, Diwakar Turaga, Iki Adachi, Xiao Li, James F. Martin</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='research_article'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel4' name='research_article'> <strong></strong> <span class='toggle-icon'></span> Research Articles </a> <div class='content active' id='panel4'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/171164">YAP1 induces bladder cancer progression and promotes immune evasion through IL-6/STAT3 pathway and CXCL deregulation</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/171164">Pritam Sadhukhan, … , David McConkey, Mohammad Hoque</a> <a class='hide-for-small show-more' data-reveal-id='article45698-more' href='#'> <div class='article-authors'> Pritam Sadhukhan, … , David McConkey, Mohammad Hoque </div> </a> <span class='article-published-at'> Published December 4, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e171164. <a href="https://doi.org/10.1172/JCI171164">https://doi.org/10.1172/JCI171164</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/171164">Text</a> | <a href="/articles/view/171164/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI171164' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/171164/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/171000/171164/small/JCI171164.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45698-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/171164">YAP1 induces bladder cancer progression and promotes immune evasion through IL-6/STAT3 pathway and CXCL deregulation</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/171164">Text</a></li> <li><a class="button tiny" href="/articles/view/171164/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The Hippo signaling pathway plays a key role in tumorigenesis in different cancer types. We investigated the role of the Hippo effector YAP1 in the tumor immune microenvironment (TIME) of urothelial carcinoma of the bladder (UCB) and evaluated the efficacy of immunotherapy in the context of YAP1 signaling. We performed numerous in vitro and in vivo experiments to determine the role of YAP1 using genetic and pharmacological attenuation of YAP1 activity. Briefly, RNA sequencing was carried out with mouse and human cell lines to identify novel YAP1-regulated downstream targets unbiasedly. We then experimentally confirmed that YAP1 regulates the TIME through the IL-6/STAT3 signaling pathway and varied C-X-C motif chemokine regulation. We analyzed several human sample sets to explore the TIME status in the context of YAP1 expression. Our data indicate that YAP1 attenuation decreases M2 macrophages and myeloid-derived suppressor cells in the TIME compared with YAP1-expressing cells. In summary, this study provides insights into YAP1 signaling as a driver for cancer stemness and an inducer of immunosuppressive TIME. Moreover, the therapeutic efficacy of YAP1 attenuation indicates that combined blockade of YAP1 and immune checkpoints may yield clinical value for treating patients with UCB.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Pritam Sadhukhan, Mingxiao Feng, Emily Illingworth, Ido Sloma, Akira Ooki, Andres Matoso, David Sidransky, Burles A. Johnson III, Luigi Marchionni, Fenna C.M. Sillé, Woonyoung Choi, David McConkey, Mohammad Hoque</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/174249">Targeted degradation of oncogenic KRAS<sup>G12V</sup> triggers antitumor immunity in lung cancer models</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/174249">Dezhi Li, … , Kwok-Kin Wong, Hua Zhang</a> <a class='hide-for-small show-more' data-reveal-id='article45681-more' href='#'> <div class='article-authors'> Dezhi Li, … , Kwok-Kin Wong, Hua Zhang </div> </a> <span class='article-published-at'> Published December 24, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e174249. <a href="https://doi.org/10.1172/JCI174249">https://doi.org/10.1172/JCI174249</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/174249">Text</a> | <a href="/articles/view/174249/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI174249' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/174249/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/174000/174249/small/JCI174249.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45681-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/174249">Targeted degradation of oncogenic KRAS<sup>G12V</sup> triggers antitumor immunity in lung cancer models</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/174249">Text</a></li> <li><a class="button tiny" href="/articles/view/174249/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with the G12C mutation and advanced our understanding of the function of this mutation. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V-transgenic mouse model. We explored the therapeutic potential of KRASG12V degradation and characterized its effect on the tumor microenvironment (TME). Our study reveals that degradation of KRASG12V abolished lung and pancreatic tumors in mice and caused a robust inhibition of KRAS-regulated cancer-intrinsic signaling. Importantly, targeted degradation of KRASG12V reprogrammed the TME toward a stimulatory milieu and drove antitumor immunity, elicited mainly by effector and cytotoxic CD8+ T cells. Our work provides insights into the effect of KRASG12V degradation on both tumor progression and the immune response, highlighting degraders as a powerful strategy for targeting KRAS-mutant cancers.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Dezhi Li, Ke Geng, Yuan Hao, Jiajia Gu, Saurav Kumar, Annabel T. Olson, Christina C. Kuismi, Hye Mi Kim, Yuanwang Pan, Fiona Sherman, Asia M. Williams, Yiting Li, Fei Li, Ting Chen, Cassandra Thakurdin, Michela Ranieri, Mary Meynardie, Daniel S. Levin, Janaye Stephens, Alison Chafitz, Joy Chen, Mia S. Donald-Paladino, Jaylen M. Powell, Ze-Yan Zhang, Wei Chen, Magdalena Ploszaj, Han Han, Shengqing Stan Gu, Tinghu Zhang, Baoli Hu, Benjamin A. Nacev, Medard Ernest Kaiza, Alice H. Berger, Xuerui Wang, Jing Li, Xuejiao Sun, Yang Liu, Xiaoyang Zhang, Tullia C. Bruno, Nathanael S. Gray, Behnam Nabet, Kwok-Kin Wong, Hua Zhang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/174647">Endogenous antigens shape the transcriptome and TCR repertoire in an autoimmune arthritis model</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/174647">Elizabeth E. McCarthy, … , Arthur Weiss, Judith F. Ashouri</a> <a class='hide-for-small show-more' data-reveal-id='article45699-more' href='#'> <div class='article-authors'> Elizabeth E. McCarthy, … , Arthur Weiss, Judith F. Ashouri </div> </a> <span class='article-published-at'> Published November 26, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e174647. <a href="https://doi.org/10.1172/JCI174647">https://doi.org/10.1172/JCI174647</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/174647">Text</a> | <a href="/articles/view/174647/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI174647' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/174647/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/174000/174647/small/JCI174647.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45699-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/174647">Endogenous antigens shape the transcriptome and TCR repertoire in an autoimmune arthritis model</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/174647">Text</a></li> <li><a class="button tiny" href="/articles/view/174647/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The development of pathogenic autoreactive CD4+ T cells, particularly in the context of impaired signaling, remains poorly understood. Unraveling how defective signaling pathways contribute to their activation and persistence is crucial for identifying new therapeutic targets. We performed bulk and single-cell RNA-Seq (scRNA-Seq) and single-cell T cell receptor sequencing (scTCR-Seq) to profile a highly arthritogenic subset of naive CD4+ T cells from BALB/c-Zap70*W163C (SKG) mice, which develop CD4+ T cell–mediated autoimmune arthritis driven by a hypomorphic mutation in Zap70 — a key TCR signaling kinase. Despite impaired signaling, these cells exhibited heightened expression of T cell activation and cytokine signaling genes but diminished expression of a subset of tolerogenic markers (Izumo1r, Tnfrsf9, Cd5, S100a11) compared with WT cells. The arthritogenic cells showed an enrichment for TCR variable β (Vβ) chains targeting superantigens (Sags) from the endogenous mouse mammary tumor virus (MMTV) but exhibited diminished induction of tolerogenic markers following peripheral antigen encounter, contrasting with the robust induction of the negative regulators seen in WT cells. In arthritic joints, cells expressing Sag-reactive Vβs expanded alongside detectable MMTV proviruses. Antiretroviral treatment and Sag-reactive T cell depletion curtailed SKG arthritis, suggesting that endogenous retroviruses disrupted peripheral tolerance and promoted the activation and differentiation of autoreactive CD4+ T cells into pathogenic effector cells.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Elizabeth E. McCarthy, Steven Yu, Noah Perlmutter, Yuka Nakao, Ryota Naito, Charles Lin, Vivienne Riekher, Joe DeRisi, Chun Jimmie Ye, Arthur Weiss, Judith F. Ashouri</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/175680">Low tristetraprolin expression activates phenotypic plasticity and primes transition to lethal prostate cancer in mice</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/175680">Katherine L. Morel, … , Christopher J. Sweeney, Leigh Ellis</a> <a class='hide-for-small show-more' data-reveal-id='article45704-more' href='#'> <div class='article-authors'> Katherine L. Morel, … , Christopher J. Sweeney, Leigh Ellis </div> </a> <span class='article-published-at'> Published November 19, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e175680. <a href="https://doi.org/10.1172/JCI175680">https://doi.org/10.1172/JCI175680</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/175680">Text</a> | <a href="/articles/view/175680/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI175680' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/175680/figure/1' ref='group' title='ZFP36/TTP and clinical outcomes. (A) RNA- and IHC-based forest plots depicting ZFP36/TTP expression related to clinical outcomes (biochemical recurrence and disease-free survival) and risk of lethal PCa (case-control cohorts). TCGA PRAD, The Cancer Genome Atlas Prostate Adenocarcinoma data set; DFCI FIHC, Dana-Farber Cancer Institute Fluorescent IHC; HPHS-PHS, Health Professionals Follow-up Study and Physicians’ Health Study. (B) Upregulated and downregulated genes were identified by differential expression analysis of TCGA PRAD cases divided by lower-quartile expression of ZFP36. (C) Representative images of immunofluorescent (IF) staining for pan-cytokeratin (yellow) and basal (red) markers, as well as TTP (green) in human PCa used for expression analysis. Benign glands (arrowheads) costain for pan-cytokeratin and basal cocktails; tumor cells (arrows) demonstrate absent basal expression. Far right images display diffuse prostate tumor with absent TTP expression. (D) Kaplan-Meier survival analysis demonstrating that TTP deficiency, measured by protein expression (DFCI, refs. 40, 69) and ZFP36 mRNA expression (TCGA PRAD, ref. 35; Taylor et al., ref. 34), results in shorter disease-free-survival, and even shorter disease-free survival in combination with PTEN deficiency.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/175000/175680/small/JCI175680.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45704-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/175680">Low tristetraprolin expression activates phenotypic plasticity and primes transition to lethal prostate cancer in mice</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/175680">Text</a></li> <li><a class="button tiny" href="/articles/view/175680/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Phenotypic plasticity is a hallmark of cancer and is increasingly realized as a mechanism of resistance to androgen receptor–targeted (AR-targeted) therapy. Now that many prostate cancer (PCa) patients are treated upfront with AR-targeted agents, it is critical to identify actionable mechanisms that drive phenotypic plasticity, to prevent the emergence of resistance. We showed that loss of tristetraprolin (TTP; gene ZFP36) increased NF-κB activation, and was associated with higher rates of aggressive disease and early recurrence in primary PCa. We also examined the clinical and biological impact of ZFP36 loss with co-loss of PTEN, a known driver of PCa. Analysis of multiple independent primary PCa cohorts demonstrated that PTEN and ZFP36 co-loss was associated with increased recurrence risk. Engineering prostate-specific Zfp36 deletion in vivo induced prostatic intraepithelial neoplasia, and, with Pten codeletion, resulted in rapid progression to castration-resistant adenocarcinoma. Zfp36 loss altered the cell state driven by Pten loss, as demonstrated by enrichment of epithelial–mesenchymal transition (EMT), inflammation, TNF-α/NF-κB, and IL-6–JAK/STAT3 gene sets. Additionally, our work revealed that ZFP36 loss also induced enrichment of multiple gene sets involved in mononuclear cell migration, chemotaxis, and proliferation. Use of the NF-κB inhibitor dimethylaminoparthenolide (DMAPT) induced marked therapeutic responses in tumors with PTEN and ZFP36 co-loss and reversed castration resistance.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Katherine L. Morel, Beatriz Germán, Anis A. Hamid, Jagpreet S. Nanda, Simon Linder, Andries M. Bergman, Henk van der Poel, Ingrid Hofland, Elise M. Bekers, Shana Y. Trostel, Deborah L. Burkhart, Scott Wilkinson, Anson T. Ku, Minhyung Kim, Jina Kim, Duanduan Ma, Jasmine T. Plummer, Sungyong You, Xiaofeng A. Su, Wilbert Zwart, Adam G. Sowalsky, Christopher J. Sweeney, Leigh Ellis</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/177342">G-CSF resistance of <i>ELANE</i>-mutant neutropenia depends on SERF1-containing truncated–neutrophil elastase aggregates</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/177342">Ramesh C. Nayak, … , Carolyn M. Lutzko, Jose A. Cancelas</a> <a class='hide-for-small show-more' data-reveal-id='article45675-more' href='#'> <div class='article-authors'> Ramesh C. Nayak, … , Carolyn M. Lutzko, Jose A. Cancelas </div> </a> <span class='article-published-at'> Published November 19, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e177342. <a href="https://doi.org/10.1172/JCI177342">https://doi.org/10.1172/JCI177342</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/177342">Text</a> | <a href="/articles/view/177342/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI177342' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/177342/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/177000/177342/small/JCI177342.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45675-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/177342">G-CSF resistance of <i>ELANE</i>-mutant neutropenia depends on SERF1-containing truncated–neutrophil elastase aggregates</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/177342">Text</a></li> <li><a class="button tiny" href="/articles/view/177342/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Severe congenital neutropenia (SCN) is frequently associated with dominant point mutations in ELANE, the gene encoding neutrophil elastase (NE). Chronic administration of granulocyte colony–stimulating factor (G-CSF) is a first-line treatment of ELANE-mutant (ELANEmut) SCN. However, some ELANEmut patients, including patients with ELANE start codon mutations, do not respond to G-CSF. Here, through directed granulopoiesis of gene-edited isogenic normal and patient-derived iPSCs, we demonstrate that ELANE start codon mutations suffice to induce G-CSF–resistant granulocytic precursor cell death and refractory SCN. ELANE start codon–mutated neutrophil precursors express predominantly nuclear N-terminally truncated alternate NE. Unlike G-CSF–sensitive ELANE mutations that induce endoplasmic reticulum and unfolded protein response stress, we found that the mutation of the ELANE translation initiation codon resulted in NE aggregates and activated proapoptotic aggrephagy, as determined by downregulated BAG1 expression, decreased BAG1/BAG3 ratio, NE colocalization with BAG3, and localized expression of autophagic LC3B. We found that SERF1, an RNA-chaperone protein, known to localize in misfolded protein aggregates in neurodegenerative diseases, was highly upregulated and interacted with cytoplasmic NE of mutant neutrophil precursors. Silencing of SERF1 enhanced survival and differentiation of iPSC-derived neutrophil precursors, restoring their responsiveness to G-CSF. These observations provide a mechanistic insight into G-CSF–resistant ELANEmut SCN, revealing targets for therapeutic intervention.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Ramesh C. Nayak, Sana Emberesh, Lisa R. Trump, Ashley M. Wellendorf, Abhishek K. Singh, Brice Korkmaz, Marshall S. Horwitz, Kasiani C. Myers, Theodosia A. Kalfa, Carolyn M. Lutzko, Jose A. Cancelas</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/177824">Tumor cell–derived spermidine promotes a protumorigenic immune microenvironment in glioblastoma via CD8<sup>+</sup> T cell inhibition</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/177824">Kristen E. Kay, … , Defne Bayik, Justin D. Lathia</a> <a class='hide-for-small show-more' data-reveal-id='article45694-more' href='#'> <div class='article-authors'> Kristen E. Kay, … , Defne Bayik, Justin D. Lathia </div> </a> <span class='article-published-at'> Published November 19, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e177824. <a href="https://doi.org/10.1172/JCI177824">https://doi.org/10.1172/JCI177824</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/177824">Text</a> | <a href="/articles/view/177824/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI177824' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/177824/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/177000/177824/small/JCI177824.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45694-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/177824">Tumor cell–derived spermidine promotes a protumorigenic immune microenvironment in glioblastoma via CD8<sup>+</sup> T cell inhibition</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/177824">Text</a></li> <li><a class="button tiny" href="/articles/view/177824/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly affect the immune system, but the mechanisms driving these interactions are not completely clear. Here, we demonstrate that the polyamine metabolite spermidine (SPD) was elevated in the GBM tumor microenvironment. Exogenous administration of SPD drove tumor aggressiveness in an immune-dependent manner in preclinical mouse models via reduction of CD8+ T cell frequency and reduced cytotoxic function. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in SPD synthesis, did not affect cancer cell growth in vitro but did result in extended survival. Furthermore, patients with GBM with a more favorable outcome had a significant reduction in SPD compared with patients with a poor prognosis. Our results demonstrate that SPD functions as a cancer cell–derived metabolite that drives tumor progression by reducing CD8+ T cell numbers and function.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Kristen E. Kay, Juyeun Lee, Ellen S. Hong, Julia Beilis, Sahil Dayal, Emily R. Wesley, Sofia Mitchell, Sabrina Z. Wang, Daniel J. Silver, Josephine Volovetz, Sadie Johnson, Mary McGraw, Matthew M. Grabowski, Tianyao Lu, Lutz Freytag, Vinod Narayana, Saskia Freytag, Sarah A. Best, James R. Whittle, Zeneng Wang, Ofer Reizes, Jennifer S. Yu, Stanley L. Hazen, J. Mark Brown, Defne Bayik, Justin D. Lathia</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/178198">Inhibition of aortic CX3CR1<sup>+</sup> macrophages mitigates thoracic aortic aneurysm progression in Marfan syndrome in mice</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/178198">Jiaqi Huang, … , Wei Kong, Yi Fu</a> <a class='hide-for-small show-more' data-reveal-id='article45697-more' href='#'> <div class='article-authors'> Jiaqi Huang, … , Wei Kong, Yi Fu </div> </a> <span class='article-published-at'> Published January 16, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e178198. <a href="https://doi.org/10.1172/JCI178198">https://doi.org/10.1172/JCI178198</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/178198">Text</a> | <a href="/articles/view/178198/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI178198' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/178198/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/178000/178198/small/JCI178198.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45697-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/178198">Inhibition of aortic CX3CR1<sup>+</sup> macrophages mitigates thoracic aortic aneurysm progression in Marfan syndrome in mice</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/178198">Text</a></li> <li><a class="button tiny" href="/articles/view/178198/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The pathogenesis of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is generally attributed to vascular smooth muscle cell (VSMC) pathologies. However, the role of immune cell–mediated inflammation remains elusive. Single-cell RNA sequencing identified a subset of CX3CR1+ macrophages mainly located in the intima in the aortic roots and ascending aortas of Fbn1C1041G/+ mice, further validated in MFS patients. Specific elimination of CX3CR1+ cells by diphtheria toxin in Cx3cr1-CreERT2iDTRF/+Fbn1C1041G/+ mice efficiently ameliorated TAA progression. Administering the monoclonal antibodies to respectively neutralize TNF-α and IGF1 produced by CX3CR1+ cells from MFS patients greatly suppressed the cocultured MFS patient–specific induced pluripotent stem cell–derived VSMC inflammation. BM transplantation and parabiosis revealed that CX3CR1+ macrophages are mainly originated from BM-derived monocytes. Targeting TNF-α and IGF1 in CX3CR1+ macrophages via shRNA lentivirus transduction in BM cells efficiently suppressed TAA development in BM-transplanted Fbn1C1041G/+ mice. Application of the CCR2 antagonist RS504393 to inhibit monocyte infiltration markedly reduced the accumulation of CX3CR1+ macrophages and subsequently alleviated TAA progression in Fbn1C1041G/+ mice. In summary, CX3CR1+ macrophages mainly located in aortic intima mediate TAA formation by paracrinally causing VSMC inflammation, and targeting them offers a potential antiinflammatory therapeutic strategy for MFS-related TAA.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Jiaqi Huang, Hao Liu, Zhujiang Liu, Zhenting Wang, Hanshi Xu, Zhuofan Li, Shan Huang, Xueyuan Yang, Yicong Shen, Fang Yu, Yulin Li, Junming Zhu, Wei Li, Li Wang, Wei Kong, Yi Fu</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/179436">Rapid response of lichen planus to baricitinib associated with suppression of cytotoxic CXCL13<sup>+</sup>CD8<sup>+</sup> T cells</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/179436">Angelina S. Hwang, … , Johann E. Gudjonsson, Aaron R. Mangold</a> <a class='hide-for-small show-more' data-reveal-id='article45672-more' href='#'> <div class='article-authors'> Angelina S. Hwang, … , Johann E. Gudjonsson, Aaron R. Mangold </div> </a> <span class='article-published-at'> Published November 14, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e179436. <a href="https://doi.org/10.1172/JCI179436">https://doi.org/10.1172/JCI179436</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/179436">Text</a> | <a href="/articles/view/179436/pdf">PDF</a> <span class='label-article-type'>Clinical Research and Public Health</span> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI179436' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/179436/figure/1' ref='group' title='Example image of cutaneous LP response to baricitinib (week 0 versus week 16).'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/179000/179436/small/JCI179436.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45672-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/179436">Rapid response of lichen planus to baricitinib associated with suppression of cytotoxic CXCL13<sup>+</sup>CD8<sup>+</sup> T cells</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/179436">Text</a></li> <li><a class="button tiny" href="/articles/view/179436/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>BACKGROUND Cutaneous lichen planus (LP) is a recalcitrant, difficult-to-treat, inflammatory skin disease characterized by pruritic, flat-topped, violaceous papules on the skin. Baricitinib is an oral Janus kinase (JAK) 1/2 inhibitor that interrupts the signaling pathway of IFN-γ, a cytokine implicated in the pathogenesis of LP.METHODS In this phase II trial, 12 patients with cutaneous LP received 2 mg daily baricitinib for 16 weeks, accompanied by in-depth spatial, single-cell, and bulk transcriptomic profiling of pre- and posttreatment samples.RESULTS An early and sustained clinical response was seen, with 83.3% of patients responsive at week 16. Our molecular data identified a unique, oligoclonal IFN-γ, CD8+, and CXCL13+ cytotoxic T cell population in LP skin and demonstrated a rapid decrease in IFN signature within 2 weeks of treatment, most prominently in the basal layer of the epidermis.CONCLUSION This study demonstrates the efficacy and molecular mechanisms of JAK inhibition in LP.TRIAL REGISTRATION NCT05188521FUNDING Eli Lilly, Appignani Benefactor Funds, 5P30AR075043, Mayo Clinic Clinical Trials Stimulus Funds.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Angelina S. Hwang, Jacob A. Kechter, Tran H. Do, Alysia N. Hughes, Nan Zhang, Xing Li, Rachael Bogle, Caitlin M. Brumfiel, Meera H. Patel, Blake Boudreaux, Puneet Bhullar, Shams Nassir, Miranda L. Yousif, Alyssa L. Stockard, Zachary Leibovit-Reiben, Ewoma Ogbaudu, David J. DiCaudo, Jennifer Fox, Mehrnaz Gharaee-Kermani, Xianying Xing, Samantha Zunich, Emily Branch, J. Michelle Kahlenberg, Allison C. Billi, Olesya Plazyo, Lam C. Tsoi, Mark R. Pittelkow, Johann E. Gudjonsson, Aaron R. Mangold</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/179703">An epigenetic pathway regulates MHC-II expression and function in B cell lymphoma models</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/179703">Te Zhang, … , Zibo Zhao, Lu Wang</a> <a class='hide-for-small show-more' data-reveal-id='article45693-more' href='#'> <div class='article-authors'> Te Zhang, … , Zibo Zhao, Lu Wang </div> </a> <span class='article-published-at'> Published January 16, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e179703. <a href="https://doi.org/10.1172/JCI179703">https://doi.org/10.1172/JCI179703</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/179703">Text</a> | <a href="/articles/view/179703/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI179703' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/179703/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/179000/179703/small/JCI179703.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45693-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/179703">An epigenetic pathway regulates MHC-II expression and function in B cell lymphoma models</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/179703">Text</a></li> <li><a class="button tiny" href="/articles/view/179703/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Mutations or homozygous deletions of MHC class II (MHC-II) genes are commonly found in B cell lymphomas that develop in immune-privileged sites and have been associated with patient survival. However, the mechanisms regulating MHC-II expression, particularly through genetic and epigenetic factors, are not yet fully understood. In this study, we identified a key signaling pathway involving the histone H2AK119 deubiquitinase BRCA1 associated protein 1 (BAP1), the interferon regulatory factor interferon regulatory factor 1 (IRF1), and the MHC-II transactivator class II transactivator (CIITA), which directly activates MHC-II gene expression. Disruption of the BAP1/IRF1/CIITA axis leads to a functional attenuation of MHC-II expression and MHC-II–dependent immune cell infiltration, leading to accelerated tumor growth in immunocompetent mice. Additionally, we demonstrated that pharmacological inhibition of polycomb repressive complex 1 (PRC1) — which deposits histone H2K119Ub and opposes BAP1 activity — can restore MHC-II gene expression in BAP1-deficient B cell lymphoma cells. These findings suggest that BAP1 may function as a tumor suppressor by regulating the tumor microenvironment and immune response. Our study also establishes the rationale for therapeutic strategies to restore tumor-specific MHC-II expression and enhance immunotherapy outcomes at epigenetic levels in B cell lymphoma treatment.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Te Zhang, Oguzhan Beytullahoglu, Rima Tulaiha, Amanda Luvisotto, Aileen Szczepanski, Natsumi Tsuboyama, Zibo Zhao, Lu Wang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/180622">Endothelial STING-JAK1 interaction promotes tumor vasculature normalization and antitumor immunity</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/180622">Huanling Zhang, … , Xiao-Shi Zhang, Xiaojun Xia</a> <a class='hide-for-small show-more' data-reveal-id='article45692-more' href='#'> <div class='article-authors'> Huanling Zhang, … , Xiao-Shi Zhang, Xiaojun Xia </div> </a> <span class='article-published-at'> Published January 16, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e180622. <a href="https://doi.org/10.1172/JCI180622">https://doi.org/10.1172/JCI180622</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/180622">Text</a> | <a href="/articles/view/180622/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI180622' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/180622/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/180000/180622/small/JCI180622.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45692-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/180622">Endothelial STING-JAK1 interaction promotes tumor vasculature normalization and antitumor immunity</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/180622">Text</a></li> <li><a class="button tiny" href="/articles/view/180622/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Stimulator of interferon genes (STING) agonists have been developed and tested in clinical trials for their antitumor activity. However, the specific cell population(s) responsible for such STING activation–induced antitumor immunity have not been completely understood. In this study, we demonstrated that endothelial STING expression was critical for STING agonist–induced antitumor activity. STING activation in endothelium promoted vessel normalization and CD8+ T cell infiltration — which required type I IFN (IFN-I) signaling— but not IFN-γ or CD4+ T cells. Rather than an upstream adaptor for inducing IFN-I signaling, STING acted downstream of interferon-α/β receptor (IFNAR) in endothelium for the JAK1-STAT signaling activation. Mechanistically, IFN-I stimulation induced JAK1-STING interaction and promoted JAK1 phosphorylation, which involved STING palmitoylation at the Cysteine 91 site but not its C-terminal tail (CTT) domain. Endothelial STING and JAK1 expression was significantly associated with immune cell infiltration in patients with cancer, and STING palmitoylation level correlated positively with CD8+ T cell infiltration around STING-positive blood vessels in tumor tissues from patients with melanoma. In summary, our findings uncover a previously unrecognized function of STING in regulating JAK1/STAT activation downstream of IFN-I stimulation and provide a new insight for future design and clinical application of STING agonists for cancer therapy.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Huanling Zhang, Zining Wang, Jiaxin Wu, Yong-Qiang Zheng, Qi Zhao, Shuai He, Hang Jiang, Chang Jiang, Tiantian Wang, Yongxiang Liu, Lei Cui, Hui Guo, Jiahong Yi, Huan Jin, Chunyuan Xie, Mengyun Li, Jiahui Li, Xiaojuan Wang, Liangping Xia, Xiao-Shi Zhang, Xiaojun Xia</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/180679">Progranulin-dependent repair function of regulatory T cells drives bone-fracture healing</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/180679">Ruiying Chen, … , Hongchang Lai, Junyu Shi</a> <a class='hide-for-small show-more' data-reveal-id='article45671-more' href='#'> <div class='article-authors'> Ruiying Chen, … , Hongchang Lai, Junyu Shi </div> </a> <span class='article-published-at'> Published November 7, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e180679. <a href="https://doi.org/10.1172/JCI180679">https://doi.org/10.1172/JCI180679</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/180679">Text</a> | <a href="/articles/view/180679/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI180679' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/180679/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/180000/180679/small/JCI180679.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45671-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/180679">Progranulin-dependent repair function of regulatory T cells drives bone-fracture healing</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/180679">Text</a></li> <li><a class="button tiny" href="/articles/view/180679/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Local immunoinflammatory events instruct skeletal stem cells (SSCs) to repair/regenerate bone after injury, but mechanisms are incompletely understood. We hypothesized that specialized Tregs are necessary for bone repair and interact directly with SSCs through organ-specific messages. Both in human patients with bone fracture and a mouse model of bone injury, we identified a bone injury–responding Treg subpopulation with bone-repair capacity marked by CCR8. Local production of CCL1 induced a massive migration of CCR8+ Tregs from periphery to the injury site. Depending on secretion of progranulin (PGRN), a protein encoded by the granulin (Grn) gene, CCR8+ Tregs supported the accumulation and osteogenic differentiation of SSCs and thereby bone repair. Mechanistically, we revealed that CCL1 enhanced expression levels of basic leucine zipper ATF-like transcription factor (BATF) in CCR8+ Tregs, which bound to the Grn promoter and increased Grn translational output and then PGRN secretion. Together, our work provides a new perspective in osteoimmunology and highlights possible ways of manipulating Treg signaling to enhance bone repair and regeneration.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Ruiying Chen, Xiaomeng Zhang, Bin Li, Maurizio S. Tonetti, Yijie Yang, Yuan Li, Beilei Liu, Shujiao Qian, Yingxin Gu, Qingwen Wang, Kairui Mao, Hao Cheng, Hongchang Lai, Junyu Shi</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/181143">An inducible RIPK3-driven necroptotic system enhances cancer cell–based immunotherapy and ensures safety</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/181143">Kok-Siong Chen, … , Natalia Claire Mendonca, Khalid Shah</a> <a class='hide-for-small show-more' data-reveal-id='article45702-more' href='#'> <div class='article-authors'> Kok-Siong Chen, … , Natalia Claire Mendonca, Khalid Shah </div> </a> <span class='article-published-at'> Published November 19, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e181143. <a href="https://doi.org/10.1172/JCI181143">https://doi.org/10.1172/JCI181143</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/181143">Text</a> | <a href="/articles/view/181143/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI181143' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/181143/figure/1' ref='group' title='Establishing an inducible RIPK3-driven necroptotic safety switch. (A) Coclustering of primary tumor samples (n = 2,785) in TCGA based on apoptotic (GO: 0097190) and necroptotic (GO: 0097527) signaling pathway gene signatures. (B) Survival curves showing survival probability for C1 and C2 clusters from A. The survival curves between 2 groups were compared using a log-rank (Mantel-Cox) test with Bonferroni correction. (C) Expression of HMGB1 in C1 and C2 clusters from A. (D) Coclustering of primary tumor samples (n = 222) in the CCGA based on apoptotic (GO: 0097190) and necroptotic (GO: 0097527) signaling pathway gene signatures. (E) Survival curves showing overall survival probability for C2 and C3 clusters from D. The survival curves between 2 groups were compared using a log-rank (Mantel-Cox) test with Bonferroni correction. (F) Expression of HMGB1 in C2 and C3 clusters from D. (G) Schematic representation of the RIPK3 B/B-inducible safety switch system. (H) CT2A and CT2A-RIPK3 cell viability assay following treatment with B/B in a dose-dependent manner for 6 hours and time-lapse imaging of the cells before and after treatment with 10 nM B/B for 6 hours. (I) Western blot analysis of p-MLKL, p-RIPK3, and cleaved caspase 3 levels upon B/B treatment in CT2A and CT2A-RIPK3 cells with different treatment durations. (J) Schematic of the experimental timeline for intracranial GBM cell implantation and the treatment schedule for B/B. (K) Graph of Fluc signal in C57BL6 mice after intracranial implantation of CT2A cells with B/B treatment (n = 3) and CT2A-RIPK3 cells with (n = 3) and without (n = 3) B/B treatment. Dotted line represents the B/B treatment time point. Data represent the mean ± SEM. (L) Kaplan-Meier curves showing the survival probability for C57BL6 mice after intracranial implantation with CT2A with B/B treatment (n = 3) and CT2A-RIPK3 with (n = 3) and without (n = 3) B/B treatment. *P < 0.05, ***P < 0.001, and ****P < 0.0001, by log-rank (Mantel-Cox) test with Bonferroni correction (B, E, and L) and unpaired, 2-tailed Student’s t test (C and F). RPKM, reads per kilobase per million mapped reads.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/181000/181143/small/JCI181143.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45702-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/181143">An inducible RIPK3-driven necroptotic system enhances cancer cell–based immunotherapy and ensures safety</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/181143">Text</a></li> <li><a class="button tiny" href="/articles/view/181143/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Recent progress in cancer cell–based therapies has led to effective targeting and robust immune responses against cancer. However, the inherent safety risks of using live cancer cells necessitate the creation of an optimized safety switch without hindering the efficacy of immunotherapy. The existing safety switches typically induce tolerogenic cell death, potentially leading to an immunosuppressive tumor immune microenvironment (TIME), which is counterproductive to the goals of immunotherapy. Here, we developed and characterized an inducible receptor-interacting protein kinase 3–driven (RIPK3-driven) necroptotic system that serves a dual function of safety switch as well as inducer of immunogenic cell death, which in turn stimulates antitumor immune responses. We show that activation of the RIPK3 safety switch triggered immunogenic responses marked by an increased release of ATP and damage-associated molecular patterns (DAMPs). Compared with other existing safety switches, incorporating the RIPK3 system inhibited tumor growth, improved survival outcomes in tumor-bearing mice, and fostered long-term antitumor immunity. Moreover, the RIPK3 system reinvigorated the TIME by promoting DC maturation, polarizing the macrophages toward a M1 phenotype, and reducing the exhaustion of CD4+ and CD8+ T lymphocytes. Our study highlights the dual role of the RIPK3-driven necroptotic system in improving the safety and efficacy of cancer cell–based therapy, with broader implications for cellular therapies.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Kok-Siong Chen, Sarah Manoury-Battais, Nobuhiko Kanaya, Ioulia Vogiatzi, Paulo Borges, Sterre J. Kruize, Yi-Ching Chen, Laura Y. Lin, Filippo Rossignoli, Natalia Claire Mendonca, Khalid Shah</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/183219">Ferroptosis of select skin epithelial cells initiates and maintains chronic systemic immune-mediated psoriatic disease</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/183219">Kavita Vats, … , Valerian E. Kagan, Yuri L. Bunimovich</a> <a class='hide-for-small show-more' data-reveal-id='article45682-more' href='#'> <div class='article-authors'> Kavita Vats, … , Valerian E. Kagan, Yuri L. Bunimovich </div> </a> <span class='article-published-at'> Published November 21, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e183219. <a href="https://doi.org/10.1172/JCI183219">https://doi.org/10.1172/JCI183219</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/183219">Text</a> | <a href="/articles/view/183219/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI183219' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/183219/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/183000/183219/small/JCI183219.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45682-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/183219">Ferroptosis of select skin epithelial cells initiates and maintains chronic systemic immune-mediated psoriatic disease</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/183219">Text</a></li> <li><a class="button tiny" href="/articles/view/183219/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Dysregulations of epithelial-immune interactions frequently culminate in chronic inflammatory diseases of the skin, lungs, kidneys, and gastrointestinal tract. Yet, the intraepithelial processes that initiate and perpetuate inflammation in these organs are poorly understood. Here, by utilizing redox lipidomics we identified ferroptosis-associated peroxidation of polyunsaturated phosphatidylethanolamines in the epithelia of patients with asthma, cystic fibrosis, psoriasis, and renal failure. Focusing on psoriasis as a disease model, we used high-resolution mass spectrometry imaging and identified keratin 14–expressing (K14-expressing) keratinocytes executing a ferroptotic death program in human psoriatic skin. Psoriatic phenotype with characteristic Th1/Th17 skin and extracutaneous immune responses was initiated and maintained in a murine model designed to actuate ferroptosis in a fraction of K14+ glutathione peroxidase 4–deficient (Gpx4-deficient) epidermal keratinocytes. Importantly, an antiferroptotic agent, liproxstatin-1, was as effective as clinically relevant biological IL-12/IL-23/TNF-α–targeting therapies or the depletion of T cells in completely abrogating molecular, biochemical, and morphological features of psoriasis. As ferroptosis in select epidermal keratinocytes triggers and sustains a pathological psoriatic multiorgan inflammatory circuit, we suggest that strategies targeting ferroptosis or its causes may be effective in preventing or ameliorating a variety of chronic inflammatory diseases.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Kavita Vats, Hua Tian, Kunal Singh, Yulia Y. Tyurina, Louis J. Sparvero, Vladimir A. Tyurin, Oleg Kruglov, Alexander Chang, Jiefei Wang, Felicia Green, Svetlana N. Samovich, Jiying Zhang, Ansuman Chattopadhyay, Natalie Murray, Vrusha K. Shah, Alicia R. Mathers, Uma R. Chandran, Joseph M. Pilewski, John A. Kellum, Sally E. Wenzel, Hülya Bayır, Valerian E. Kagan, Yuri L. Bunimovich</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/183331"><i>Neisseria gonorrhoeae</i> induces local secretion of IL-10 at the human cervix to promote colonization</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/183331">Yiwei Dai, … , Daniel C. Stein, Wenxia Song</a> <a class='hide-for-small show-more' data-reveal-id='article45677-more' href='#'> <div class='article-authors'> Yiwei Dai, … , Daniel C. Stein, Wenxia Song </div> </a> <span class='article-published-at'> Published November 25, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e183331. <a href="https://doi.org/10.1172/JCI183331">https://doi.org/10.1172/JCI183331</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/183331">Text</a> | <a href="/articles/view/183331/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI183331' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/183331/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/183000/183331/small/JCI183331.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45677-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/183331"><i>Neisseria gonorrhoeae</i> induces local secretion of IL-10 at the human cervix to promote colonization</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/183331">Text</a></li> <li><a class="button tiny" href="/articles/view/183331/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Gonorrhea, caused by the human-restricted pathogen Neisseria gonorrhoeae, is a commonly reported sexually transmitted infection. Since most infections in women are asymptomatic, the true number of infections is likely much higher than reported. How gonococci (GC) colonize women’s cervixes without triggering symptoms remains elusive. Using a human cervical tissue explant model, we found that GC inoculation increased the local secretion of both proinflammatory (IL-1β and TNF-α) and antiinflammatory (IL-10) cytokines during the first 24 hours of infection. Cytokine induction required GC expression of Opa isoforms that bind the host receptors carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). GC inoculation induced NF-κB activation in both cervical epithelial and subepithelial cells. However, inhibition of NF-κB activation, which reduced GC-induced IL-1β and TNF-α, did not affect GC colonization. Neutralizing IL-10 or blocking IL-10 receptors by antibodies reduced GC colonization by increasing epithelial shedding and epithelial cell-cell junction disassembly. Inhibition of the CEACAM downstream signaling molecule SHP1/2, which reduced GC colonization and increased epithelial shedding, decreased GC-induced IL-10 secretion. These results show that GC induce local secretion of IL-10, a potent antiinflammatory cytokine, at the cervix by engaging the host CEACAMs to prevent GC-colonizing epithelial cells from shedding, providing a potential mechanism for GC asymptomatic colonization in women.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yiwei Dai, Vonetta L. Edwards, Qian Yu, Hervé Tettelin, Daniel C. Stein, Wenxia Song</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/183656"><i>MAP3K1</i> mutations confer tumor immune heterogeneity in hormone receptor–positive HER2-negative breast cancer</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/183656">Yu-Wen Cai, … , Zhi-Ming Shao, Ke-Da Yu</a> <a class='hide-for-small show-more' data-reveal-id='article45695-more' href='#'> <div class='article-authors'> Yu-Wen Cai, … , Zhi-Ming Shao, Ke-Da Yu </div> </a> <span class='article-published-at'> Published November 12, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e183656. <a href="https://doi.org/10.1172/JCI183656">https://doi.org/10.1172/JCI183656</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/183656">Text</a> | <a href="/articles/view/183656/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI183656' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/183656/figure/1' ref='group' title='MAP3K1 mutation is closely correlated with immune microenvironment heterogeneity in HR+/HER2– breast cancer. (A) Flowchart of bioinformatics analyses performed in the study. (B) Heatmap showing the relative abundance of immune and stromal cells calculated by MCP-Counter in each sample in CBCGA cohort (n = 351). The 2 immunological subtypes were annotated. (C) Comparison of tumor mutation burden (TMB) of tumors with the ICold and IHot subtypes in CBCGA cohort (n = 314). The center line represents the median. (D and E) Comparison of ki67 index (D) and CD274 mRNA expression level (E) of tumors with the ICold and IHot subtypes in CBCGA cohort (n = 350). The center line represents the median. (F and G) Pathological complete response (pCR) rate of patients with the ICold and IHot subtypes in the anti-PD-L1 (F) and anti-PD-1 (G) treatment arm of the I-SPY2 clinical trial. (H) The somatic mutations identified in tumors with the ICold and IHot subtypes in CBCGA cohort (n = 314). *P < 0.05. (I) Venn diagram showing genes with significantly different mutation prevalence between the ICold and IHot subtypes in CBCGA (n = 314), TCGA HR+/HER2– (n = 475), and METABRIC HR+/HER2– (n = 611) breast cancer cohorts. (J and K) Abundance of CD8+ T cells calculated by CIBERSORT (J) and GZMA mRNA expression (K) in HR+/HER2– breast tumors with or without MAP3K1 mutation in the TCGA cohort (n = 481). Statistical analysis: (C, E, J, and K) Wilcoxon signed-rank test; (D) χ2 test for trend; (F–H) Fisher’s exact test. ICold, immune cold subtype; IHot, immune hot subtype; TMB, tumor mutation burden; HR, hormone receptor; HER2, human epidermal growth factor receptor 2.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/183000/183656/small/JCI183656.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45695-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/183656"><i>MAP3K1</i> mutations confer tumor immune heterogeneity in hormone receptor–positive HER2-negative breast cancer</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/183656">Text</a></li> <li><a class="button tiny" href="/articles/view/183656/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Treatment for hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) breast cancer, the most common type of breast cancer, has faced challenges such as endocrine therapy resistance and distant relapse. Immunotherapy has shown progress in treating triple-negative breast cancer, but immunological research on HR+/HER2– breast cancer is still in its early stages. Here, we performed a multi-omics analysis of a large cohort of patients with HR+/HER2– breast cancer (n = 351) and revealed that HR+/HER2– breast cancer possessed a highly heterogeneous tumor immune microenvironment. Notably, the immunological heterogeneity of HR+/HER2– breast cancer was related to mitogen-activated protein kinase kinase kinase 1 (MAP3K1) mutation and we validated experimentally that a MAP3K1 mutation could attenuate CD8+ T cell–mediated antitumor immunity. Mechanistically, MAP3K1 mutation suppressed MHC-I–mediated tumor antigen presentation through promoting the degradation of antigen peptide transporter 1/2 (TAP1/2) mRNA, thereby driving tumor immune escape. In preclinical models, the postbiotic tyramine could reverse the MAP3K1 mutation–induced MHC-I reduction, thereby augmenting the efficacy of immunotherapy. Collectively, our study identified the vital biomarker driving the immunological heterogeneity of HR+/HER2– breast cancer and elucidated the underlying molecular mechanisms, which provided the promise of tyramine as what we believe to be a novel therapeutic strategy to enhance the efficacy of immunotherapy.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yu-Wen Cai, Cui-Cui Liu, Yan-Wu Zhang, Yi-Ming Liu, Lie Chen, Xin Xiong, Zhi-Ming Shao, Ke-Da Yu</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/183776">Clonal analysis of SepSecS-specific B and T cells in autoimmune hepatitis</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/183776">Michael Kramer, … , Benedetta Terziroli Beretta-Piccoli, Federica Sallusto</a> <a class='hide-for-small show-more' data-reveal-id='article45684-more' href='#'> <div class='article-authors'> Michael Kramer, … , Benedetta Terziroli Beretta-Piccoli, Federica Sallusto </div> </a> <span class='article-published-at'> Published January 16, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e183776. <a href="https://doi.org/10.1172/JCI183776">https://doi.org/10.1172/JCI183776</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/183776">Text</a> | <a href="/articles/view/183776/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI183776' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/183776/figure/1' ref='group' title='Characterization of anti-SLA positivity in AIH. (A and B) Measurement of SepSecS-specific IgG in plasma from patients with AIH and individuals in the healthy control group by an in-house–developed flow cytometry assay based on SepSecS/eGFP-transfected EXPI-293 cells (A) or by an in-house–developed ELISA using SepSecS produced in EXPI-293 cells (B). Note that patient AIH18 was classified anti-SLA negative in the clinical laboratory but is anti-SLA positive in both of our assays. (C and D) Scatterplots showing the correlation between the EDF50 values of SepSecS-specific IgG measured using the flow cytometry assay and ELISA (C) and the ELISA and a commercially available ELISA (cELISA) (D). (E) SepSecS-specific IgG+ memory B cells in peripheral blood of patients with AIH and individuals in the healthy control group. PBMCs (3 × 104; AIH11: 2 × 104) were plated in 192 replicate wells (AIH11, 96) and stimulated with IL-2 and the TLR 7/8 agonist R848. After 12 days, the supernatant of each well was screened for the presence of secreted SepSecS-specific IgG using the flow cytometry assay. Reported is the mean fluorescence intensity (MFI) GFP-SepSecS+ / MFI GFP-SepSecS– ratios for each individual supernatant (positive > 1.1). (F) Number of SepSecS-specific IgG+ memory B cells in 1 × 106 PBMCs in patients with AIH and individulals in the healthy control group with positive cultures in the analysis in E and calculated according to the Poisson distribution.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/183000/183776/small/JCI183776.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45684-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/183776">Clonal analysis of SepSecS-specific B and T cells in autoimmune hepatitis</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/183776">Text</a></li> <li><a class="button tiny" href="/articles/view/183776/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Autoimmune hepatitis (AIH) is a rare chronic inflammatory liver disease characterized by the presence of autoantibodies, including those targeting O-phosphoseryl-tRNA:selenocysteine-tRNA synthase (SepSecS), also known as soluble liver antigen (SLA). Anti-SepSecS antibodies have been associated with a more severe phenotype, suggesting a key role for the SepSecS autoantigen in AIH. To analyze the immune response to SepSecS in patients with AIH at the clonal level, we combined sensitive high-throughput screening assays with the isolation of monoclonal antibodies (mAbs) and T cell clones. The anti-SepSecS mAbs isolated were primarily IgG1, affinity-matured compared with their germline versions, and recognized at least 3 nonoverlapping epitopes. SepSecS-specific CD4+ T cell clones were found in patients with AIH who were anti-SLA-positive and anti-SLA-negative,and, to a lesser extent, in patients with non-AIH liver diseases and in healthy individuals. SepSecS-specific T cell clones from patients with AIH produced IFN-γ, IL-4, and IL-10, targeted multiple SepSecS epitopes, and, in one patient, were clonally expanded in both blood and liver biopsy. Finally, SepSecS-specific B cell clones, but not those of unrelated specificities, were able to present soluble SepSecS to specific T cells. Collectively, our study provides the first detailed analysis of B and T cell repertoires targeting SepSecS in patients with AIH, offering a rationale for improved targeted therapies.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Michael Kramer, Federico Mele, Sandra Jovic, Blanca Maria Fernandez, David Jarrossay, Jun Siong Low, Christiane Sokollik, Magdalena Filipowicz Sinnreich, Sylvie Ferrari-Lacraz, Giorgina Mieli-Vergani, Diego Vergani, Antonio Lanzavecchia, Antonino Cassotta, Benedetta Terziroli Beretta-Piccoli, Federica Sallusto</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/183952">Assessing advances in three decades of clinical antiretroviral therapy on the HIV-1 reservoir</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/183952">Irene González-Navarro, … , Maria Salgado, the NIH Reversing Immune Dysfunction for HIV-1 Eradication (RID-HIV) Collaboratory Group</a> <a class='hide-for-small show-more' data-reveal-id='article45703-more' href='#'> <div class='article-authors'> Irene González-Navarro, … , Maria Salgado, the NIH Reversing Immune Dysfunction for HIV-1 Eradication (RID-HIV) Collaboratory Group </div> </a> <span class='article-published-at'> Published November 29, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e183952. <a href="https://doi.org/10.1172/JCI183952">https://doi.org/10.1172/JCI183952</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/183952">Text</a> | <a href="/articles/view/183952/pdf">PDF</a> <span class='label-article-type'>Clinical Research and Public Health</span> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI183952' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/183952/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/183000/183952/small/JCI183952.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45703-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/183952">Assessing advances in three decades of clinical antiretroviral therapy on the HIV-1 reservoir</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/183952">Text</a></li> <li><a class="button tiny" href="/articles/view/183952/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>BACKGROUND Antiretroviral therapy (ART) has improved the clinical management of HIV-1 infection. However, little is known about how the latest ART recommendations affect the heterogeneity of the HIV-1 reservoir size.METHODS We used a complete statistical approach to outline parameters underlying the diversity in HIV-1 reservoir size in a cohort of 892 people with HIV-1 (PWH) on suppressive ART for more than 3 years. Total HIV-1–DNA levels were measured in PBMCs using digital droplet PCR (ddPCR).RESULTS We classified 179 (20%) participants as being low viral reservoir treated (LoViReT) (<50 HIV-1–DNA copies/106 PBMCs). Twenty variables were collected to explore their association with the LoViReT phenotype using machine learning approaches. LoViReT status was closely associated with higher nadir CD4, lower zenith pre-ART viral load, lower CD4 recovery, shorter time from diagnosis to undetectable viral load, and initiation of treatment with an integrase inhibitor–containing (InSTI-containing) regimen. Initiation of ART with any InSTI was also linked with a shorter time to undetectable viremia. Locally estimated scatterplot smoothing (LOESS) regression revealed a progressive reduction in the size of the HIV-1 reservoir in individuals who started ART after 2007. Similarly, a higher nadir CD4 and a shorter time to undetectable viremia were observed when treatment was initiated after that year.CONCLUSION Our findings demonstrate that the progressive implementation of earlier, universal treatment at diagnosis and the use of InSTIs affected the size of the HIV-1 reservoir. Our work shows that effective management of infection is the first step toward reducing the reservoir and brings us closer to achieving a cure.FUNDING NIH; Division of AIDS at the National Institute of Allergy and Infectious Diseases (NIAID), NIH; Merck Sharp & Dohme.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Irene González-Navarro, Víctor Urrea, Cristina Gálvez, Maria del Carmen Garcia-Guerrero, Sara Morón-López, Maria C. Puertas, Eulàlia Grau, Beatriz Mothe, Lucía Bailón, Cristina Miranda, Felipe García, Lorna Leal, Linos Vandekerckhove, Vincent C. Marconi, Rafick P. Sekaly, Bonaventura Clotet, Javier Martinez-Picado, Maria Salgado, the NIH Reversing Immune Dysfunction for HIV-1 Eradication (RID-HIV) Collaboratory Group</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/184929"><i>Fgfr3</i> enhancer deletion markedly improves all skeletal features in a mouse model of achondroplasia</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/184929">Marco Angelozzi, … , Andrew M. Bloh, Véronique Lefebvre</a> <a class='hide-for-small show-more' data-reveal-id='article45686-more' href='#'> <div class='article-authors'> Marco Angelozzi, … , Andrew M. Bloh, Véronique Lefebvre </div> </a> <span class='article-published-at'> Published January 16, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e184929. <a href="https://doi.org/10.1172/JCI184929">https://doi.org/10.1172/JCI184929</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/184929">Text</a> | <a href="/articles/view/184929/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI184929' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/184929/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/184000/184929/small/JCI184929.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45686-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/184929"><i>Fgfr3</i> enhancer deletion markedly improves all skeletal features in a mouse model of achondroplasia</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/184929">Text</a></li> <li><a class="button tiny" href="/articles/view/184929/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Achondroplasia, the most prevalent short-stature disorder, is caused by missense variants overactivating the fibroblast growth factor receptor 3 (FGFR3). As current surgical and pharmaceutical treatments only partially improve some disease features, we sought to explore a genetic approach. We show that an enhancer located 29 kb upstream of mouse Fgfr3 (–29E) is sufficient to confer a transgenic mouse reporter with a domain of expression in cartilage matching that of Fgfr3. Its CRISPR/Cas9-mediated deletion in otherwise WT mice reduced Fgfr3 expression in this domain by half without causing adverse phenotypes. Importantly, its deletion in mice harboring the ortholog of the most common human achondroplasia variant largely normalized long bone and vertebral body growth, markedly reduced spinal canal and foramen magnum stenosis, and improved craniofacial defects. Consequently, mouse achondroplasia is no longer lethal, and adults are overall healthy. These findings, together with high conservation of –29E in humans, open a path to develop genetic therapies for people with achondroplasia.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Marco Angelozzi, Arnaud Molin, Anirudha Karvande, Ángela Fernández-Iglesias, Samantha Whipple, Andrew M. Bloh, Véronique Lefebvre</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='corrigendum'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel5' name='corrigendum'> <strong></strong> <span class='toggle-icon'></span> Corrigendum </a> <div class='content active' id='panel5'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/190291">Parkin activates innate immunity and promotes antitumor immune responses</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/190291">Michela Perego, … , Noam Auslander, Dario C. Altieri</a> <a class='hide-for-small show-more' data-reveal-id='article45667-more' href='#'> <div class='article-authors'> Michela Perego, … , Noam Auslander, Dario C. Altieri </div> </a> <span class='article-published-at'> Published January 16, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e190291. <a href="https://doi.org/10.1172/JCI190291">https://doi.org/10.1172/JCI190291</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/190291">Text</a> | <a href="/articles/view/190291/pdf">PDF</a> | <a href="/articles/view/180983">Amended Article</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI190291' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45667-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/190291">Parkin activates innate immunity and promotes antitumor immune responses</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/190291">Text</a></li> <li><a class="button tiny" href="/articles/view/190291/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p></p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Michela Perego, Minjeong Yeon, Ekta Agarwal, Andrew T. Milcarek, Irene Bertolini, Chiara Camisaschi, Jagadish C. Ghosh, Hsin-Yao Tang, Nathalie Grandvaux, Marcus Ruscetti, Andrew V. Kossenkov, Sarah Preston-Alp, Italo Tempera, Noam Auslander, Dario C. 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