Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes

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Understanding the interplay of these cells with other immune components and the species-specific differences between mice and humans is of clinical importance. Protective responses to microorganisms involve the nonspecific but rapid defence mechanisms of the innate immune system, followed by the specific but slow defence mechanisms of the adaptive immune system. Located as sentinels at the interface between the circulation and lymphoid tissue, splenic marginal zone B cells rapidly respond to blood-borne antigens by adopting 'crossover' defensive strategies that blur the conventional boundaries of innate and adaptive immunity. This Review discusses how marginal zone B cells function as innate-like lymphocytes that mount rapid antibody responses to both T cell-dependent and T cell-independent antigens. 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</svg> </li><li class="c-breadcrumbs__item" id="breadcrumb3" itemprop="itemListElement" itemscope itemtype="https://schema.org/ListItem"> <span itemprop="name">article</span><meta itemprop="position" content="4"></li> </ol> </div> </nav> </div> <div class="u-container u-mt-32 u-mb-32 u-clearfix" id="content" data-component="article-container" data-container-type="article"> <main class="c-article-main-column u-float-left js-main-column" data-track-component="article body"> <article lang="en"> <div class="c-article-header"> <header> <ul class="c-article-identifiers" data-test="article-identifier"> <li class="c-article-identifiers__item" data-test="article-category">Review Article</li> <li class="c-article-identifiers__item">Published: <time datetime="2013-01-25">25 January 2013</time></li> </ul> <h1 class="c-article-title" data-test="article-title" data-article-title="">Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes</h1> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Andrea-Cerutti-Aff1-Aff2-Aff3" data-author-popup="auth-Andrea-Cerutti-Aff1-Aff2-Aff3" data-author-search="Cerutti, Andrea" data-corresp-id="c1">Andrea Cerutti<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff3">3</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Montserrat-Cols-Aff2" data-author-popup="auth-Montserrat-Cols-Aff2" data-author-search="Cols, Montserrat">Montserrat Cols</a><sup class="u-js-hide"><a href="#Aff2">2</a></sup> & </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Irene-Puga-Aff3" data-author-popup="auth-Irene-Puga-Aff3" data-author-search="Puga, Irene">Irene Puga</a><sup class="u-js-hide"><a href="#Aff3">3</a></sup> </li></ul> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/nri" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Nature Reviews Immunology</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 13</b>, <span class="u-visually-hidden">pages </span>118–132 (<span data-test="article-publication-year">2013</span>)<a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">32k <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="citation-count"> <p class="c-article-metrics-bar__count">535 <span class="c-article-metrics-bar__label">Citations</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">15 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/nri3383/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> <div class="u-js-hide" data-component="article-subject-links"> <h3 class="c-article__sub-heading">Subjects</h3> <ul class="c-article-subject-list"> <li class="c-article-subject-list__subject"><a href="/subjects/adaptive-immunity" data-track="click" data-track-action="view subject" data-track-label="link">Adaptive immunity</a></li><li class="c-article-subject-list__subject"><a href="/subjects/b-cells" data-track="click" data-track-action="view subject" data-track-label="link">B cells</a></li><li class="c-article-subject-list__subject"><a href="/subjects/inflammation" data-track="click" data-track-action="view subject" data-track-label="link">Inflammation</a></li><li class="c-article-subject-list__subject"><a href="/subjects/innate-immunity" data-track="click" data-track-action="view subject" data-track-label="link">Innate immunity</a></li><li class="c-article-subject-list__subject"><a href="/subjects/marginal-zone-b-cells" data-track="click" data-track-action="view subject" data-track-label="link">Marginal zone B cells</a></li><li class="c-article-subject-list__subject"><a href="/subjects/signal-transduction" data-track="click" data-track-action="view subject" data-track-label="link">Signal transduction</a></li> </ul> </div> </div> <div class="c-article-body"> <section aria-labelledby="Abs1" data-title="Key Points" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Key Points</h2><div class="c-article-section__content" id="Abs1-content"> <ul class="u-list-style-bullet"> <li> <p>Marginal zone (MZ) B cells are strategically located at the interface between the circulation and the white pulp of the spleen, where they provide a first line of defence by rapidly producing IgM and class-switched IgG antibodies in response to infections by blood-borne viruses and encapsulated bacteria. Mouse MZ B cells primarily express a non-mutated B cell receptor (BCR) and enter the circulation only to shuttle antigens to the follicle, whereas human MZ B cells express a mutated BCR and extensively recirculate.</p> </li> <li> <p>MZ B cells may also produce IgM and class-switched IgG and IgA antibodies in response to commensal antigens that physiologically translocate from the intestinal mucosa to the general circulation in the absence of infection. This innate-like humoral response may generate a ready-to-use pre-immune antibody repertoire that provides a rapid systemic line of defence not only against pathogens, but also against commensal bacteria that breach the mucosal barrier.</p> </li> <li> <p>In mice, MZ B cells originate from splenic transitional stage 2 B cells via a pathway involving the BCR, the B cell-activating factor (BAFF) receptor and the receptor NOTCH2. In humans, some MZ B cells may arise from immature or transitional B cells located in the liver and mesenteric lymph nodes via a fetal pathway involving NOTCH2, whereas other MZ B cells may emerge from transitional or germinal centre B cells located in the spleen through a postnatal pathway involving the BCR, Toll-like receptors (TLRs) and CD40.</p> </li> <li> <p>MZ B cells have a lower activation threshold than follicular B cells, which permits the rapid initiation of IgM production and of IgG- and IgA-inducing class-switch recombination (CSR) in the absence of CD40-dependent help from T follicular helper (T<sub>FH</sub>) cells. This T cell-independent pathway requires dual BCR and TLR engagement by conserved microbial antigens together with co-stimulatory signals from dendritic cells, macrophages and neutrophils via various cytokines, including BAFF, a proliferation-inducing ligand (APRIL), interleukin-6 (IL-6), IL-10, IL-21, interferon-α (IFNα), IFNβ and CXC-chemokine ligand 10 (CXCL10).</p> </li> <li> <p>MZ B cells can also undergo T cell-dependent antibody production by following either a follicular pathway involving CD40-dependent help from germinal centre T<sub>FH</sub> cells or an extrafollicular pathway involving CD40-dependent help from extrafollicular T<sub>FH</sub> cells or invariant natural killer T (iNKT) cells. In addition to expressing CD40 ligand, T<sub>FH</sub> and iNKT cells secrete various CSR- and antibody-inducing cytokines, including IL-4, IL-21 and IFNγ.</p> </li> <li> <p>In humans, MZ B cells probably have a heterogeneous ontogeny and can undergo somatic hypermutation both before and after birth through either an extrafollicular T cell-independent or a follicular T cell-dependent pathway. The extrafollicular T cell-independent pathway diversifies MZ B cells mainly during fetal life or after postnatal exposure to conserved commensal antigens or native polysaccharides, whereas the follicular T cell-dependent pathway may diversify MZ B cells predominantly after postnatal exposure to proteins or protein-conjugated polysaccharides.</p> </li> </ul> </div></div></section><section aria-labelledby="Abs3" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs3-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs3">Abstract</h2><div class="c-article-section__content" id="Abs3-content"><p>Protective responses to microorganisms involve the nonspecific but rapid defence mechanisms of the innate immune system, followed by the specific but slow defence mechanisms of the adaptive immune system. Located as sentinels at the interface between the circulation and lymphoid tissue, splenic marginal zone B cells rapidly respond to blood-borne antigens by adopting 'crossover' defensive strategies that blur the conventional boundaries of innate and adaptive immunity. This Review discusses how marginal zone B cells function as innate-like lymphocytes that mount rapid antibody responses to both T cell-dependent and T cell-independent antigens. 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class="c-article-section" id="Bib1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Bib1">References</h2><div class="c-article-section__content" id="Bib1-content"><div data-container-section="references"><ol class="c-article-references" data-track-component="outbound reference" data-track-context="references section"><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="1"><p class="c-article-references__text" id="ref-CR1">Janeway, C. 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Dr. Aiguader 88, 08003, Barcelona, Spain</p><p class="c-article-author-affiliation__authors-list">Andrea Cerutti</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Department of Medicine, The Immunology Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, 10029, New York, USA</p><p class="c-article-author-affiliation__authors-list">Andrea Cerutti & Montserrat Cols</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona Biomedical Research Park, Av. Dr. Aiguader 88, 08003, Barcelona, Spain</p><p class="c-article-author-affiliation__authors-list">Andrea Cerutti & Irene Puga</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Andrea-Cerutti-Aff1-Aff2-Aff3"><span class="c-article-authors-search__title u-h3 js-search-name">Andrea Cerutti</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Andrea%20Cerutti" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Andrea%20Cerutti" data-track="click" data-track-action="author link - 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pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Montserrat%20Cols%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Irene-Puga-Aff3"><span class="c-article-authors-search__title u-h3 js-search-name">Irene Puga</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Irene%20Puga" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Irene%20Puga" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Irene%20Puga%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li></ol></div><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding author</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:acerutti@imim.es">Andrea Cerutti</a>.</p></div></div></section><section data-title="Ethics declarations"><div class="c-article-section" id="ethics-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="ethics">Ethics declarations</h2><div class="c-article-section__content" id="ethics-content"> <h3 class="c-article__sub-heading">Competing interests</h3> <p>The authors declare no competing financial interests.</p> </div></div></section><section aria-labelledby="appendices"><div class="c-article-section" id="appendices-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="appendices">Related links</h2><div class="c-article-section__content" id="appendices-content"><h3 class="c-article__sub-heading u-visually-hidden" id="App1">Related links</h3><h3 class="c-article__sub-heading" id="Sec6">FURTHER INFORMATION</h3><p> <a href="http://www.icrea.cat/Web/ScientificStaff/Andrea-Cerutti-452">Andrea Cerutti's homepage 1</a> </p><p> <a href="http://www.mountsinai.org/profiles/andrea-cerutti">Andrea Cerutti's homepage 2</a> </p></div></div></section><section data-title="Glossary"><div class="c-article-section" id="glossary-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="glossary">Glossary</h2><div class="c-article-section__content" id="glossary-content"><dl class="c-description-list"><dt class="c-description-list__term u-text-bold" id="Glos1">Toll-like receptors</dt><dd class="c-description-list__description u-pl-32"> <p>(TLRs). A large family of germline-encoded pattern-recognition receptors that initiate innate and adaptive immune responses after recognizing conserved molecular signatures associated with microorganisms.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos2">B cell receptors</dt><dd class="c-description-list__description u-pl-32"> <p>(BCRs). A term that refers to transmembrane immunoglobulin molecules irrespective of their heavy-chain constant region.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos3">B-1 cells</dt><dd class="c-description-list__description u-pl-32"> <p>IgM<sup>hi</sup>IgD<sup>low</sup>MAC1<sup>+</sup>B220<sup>low</sup>CD23<sup>−</sup> cells that are dominant in the peritoneal and pleural cavities. Their precursors develop in the fetal liver and omentum, and in adult mice the size of the B-1 cell population is kept constant owing to the self-renewing capacity of these cells. B-1 cells recognize self components, as well as common bacterial antigens, and they secrete antibodies that tend to have a low affinity and broad specificity.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos4">Metallophilic macrophages</dt><dd class="c-description-list__description u-pl-32"> <p>A subset of macrophages that is located at the border of the white pulp and the marginal zone of the spleen. These cells are stained by silver impregnation, which explains the name.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos5">C-type lectin receptors</dt><dd class="c-description-list__description u-pl-32"> <p>(CLRs). A large family of germline-encoded pattern-recognition receptors that initiate innate and adaptive immune responses after recognizing specific conserved molecular signatures associated with microorganisms.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos6">Peyer's patches</dt><dd class="c-description-list__description u-pl-32"> <p>Groups of lymphoid nodules present in the small intestine that are massed together on the intestinal wall, opposite the line of attachment of the mesentery. Peyer's patches consist of a subepithelial dome area, B cell follicles and interfollicular T cell zones.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos7">Class-switch recombination</dt><dd class="c-description-list__description u-pl-32"> <p>(CSR). A switch in the DNA that encodes the constant region of the immunoglobulin heavy chain, from Cμ (which encodes the constant region of IgM) to Cγ, Cα or Cε, which encode the constant regions of IgG, IgA and IgE, respectively. This is accomplished through an intrachromosomal deletional rearrangement.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos8">Somatic hypermutation</dt><dd class="c-description-list__description u-pl-32"> <p>(SHM). A unique mutation mechanism that is targeted to the variable regions of rearranged immunoglobulin gene segments. Combined with selection for B cells that produce high-affinity antibodies, SHM leads to the affinity maturation of B cells in germinal centres.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos9">Congenital asplenia</dt><dd class="c-description-list__description u-pl-32"> <p>A genetic deficiency of unknown origin in humans that results in the absence of splenic development and is frequently associated with cardiovascular malformations.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos10">Natural antibodies</dt><dd class="c-description-list__description u-pl-32"> <p>Antibodies spontaneously released by B-1 cells and marginal zone B cells in the absence of immunization or infection. These antibodies have a low affinity and broad specificity for conserved self and microbial antigens and mostly belong to the IgM class, but also include IgG and IgA, particularly in humans.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos11">Transitional B cells</dt><dd class="c-description-list__description u-pl-32"> <p>Refers to transitional stage 1 (T1) and transitional stage 2 (T2) B cells, which are immature, newly formed B cells that are present in the bone marrow, blood and spleen and give rise to marginal zone and follicular B cells.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos12">Follicular dendritic cells</dt><dd class="c-description-list__description u-pl-32"> <p>(FDCs). Cells with a dendritic morphology that are present in lymph nodes. These cells display on their surface intact antigens that are held in immune complexes, and B cells in the lymph node can interact with these antigens. FDCs are of non-haematopoietic origin and are not related to dendritic cells.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos13">T cell-independent pathway</dt><dd class="c-description-list__description u-pl-32"> <p>(TI pathway). A pathway followed by B cells to produce antibodies specific for TI antigens such as microbial LPS and capsular polysaccharides. The pathway usually involves extrafollicular marginal zone B cells and B-1 cells and does not require help from T cells.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos14">T cell-dependent pathway</dt><dd class="c-description-list__description u-pl-32"> <p>(TD pathway). A pathway followed by B cells to produce antibodies specific for TD antigens such as microbial proteins. The pathway usually involves follicular B cells and requires help from T cells expressing CD40 ligand. However, extrafollicular marginal zone B cells can also respond to TD antigens.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos15">AID</dt><dd class="c-description-list__description u-pl-32"> <p>(Activation-induced cytidine deaminase). A DNA cytidine deaminase that mediates somatic hypermutation and class-switch recombination.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos16">T follicular helper cells</dt><dd class="c-description-list__description u-pl-32"> <p>(T<sub>FH</sub> cells). CD4<sup>+</sup> T helper cells that are essential for the induction of class switching in the germinal centres of secondary follicles during antibody responses to T cell-dependent antigens.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos17">Hyper-IgM syndrome</dt><dd class="c-description-list__description u-pl-32"> <p>(HIGM syndrome). A congenital immunodeficiency characterized by defective immunoglobulin heavy-chain class switching and increased IgM production. The underlying molecular defect involves CD40 ligand (in HIGM1), activation-induced cytidine deaminase (in HIGM2), CD40 (in HIGM3), uracil DNA glycosylase (in HIGM4) or other unknown B cell proteins (in HIGM5).</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos18">Germinal centre</dt><dd class="c-description-list__description u-pl-32"> <p>A lymphoid structure that arises in follicles after exposure to T cell-dependent protein antigens. This structure fosters the induction of B cell clonal expansion, class-switch recombination and somatic hypermutation, followed by the development of memory B cells and long-lived plasma cells that express high-affinity antibodies.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos19">Invariant natural killer T cells</dt><dd class="c-description-list__description u-pl-32"> <p>(iNKT cells). A subset of innate-like lymphocytes expressing an invariant Vα14<sup>+</sup> T cell receptor that recognizes soluble glycolipids loaded on the non-polymorphic MHC class I-like molecule CD1d. In humans, CD1c might serve the same function that CD1d has in mice.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos20">Innate response activator B cells</dt><dd class="c-description-list__description u-pl-32"> <p>B-1 cell-derived plasmablasts that populate perifollicular areas of both mouse and human spleens and secrete the cytokine GM-CSF.</p> </dd><dt class="c-description-list__term u-text-bold" id="Glos21">Neutrophil extracellular trap</dt><dd class="c-description-list__description u-pl-32"> <p>(NET). A set of extracellular fibres produced by an activated neutrophil to ensnare invading microorganisms. NETs enhance neutrophil-mediated killing of extracellular pathogens while minimizing damage to host cells.</p> </dd></dl></div></div></section><section data-title="Rights and permissions"><div class="c-article-section" id="rightslink-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="rightslink">Rights and permissions</h2><div class="c-article-section__content" id="rightslink-content"><p class="c-article-rights"><a data-track="click" data-track-action="view rights and permissions" data-track-label="link" href="https://s100.copyright.com/AppDispatchServlet?title=Marginal%20zone%20B%20cells%3A%20virtues%20of%20innate-like%20antibody-producing%20lymphocytes&author=Andrea%20Cerutti%20et%20al&contentID=10.1038%2Fnri3383&copyright=Springer%20Nature%20Limited&publication=1474-1733&publicationDate=2013-01-25&publisherName=SpringerNature&orderBeanReset=true">Reprints and permissions</a></p></div></div></section><section aria-labelledby="article-info" data-title="About this article"><div class="c-article-section" id="article-info-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="article-info">About this article</h2><div class="c-article-section__content" id="article-info-content"><div class="c-bibliographic-information"><div class="c-bibliographic-information__column"><h3 class="c-article__sub-heading" id="citeas">Cite this article</h3><p class="c-bibliographic-information__citation">Cerutti, A., Cols, M. & Puga, I. Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. <i>Nat Rev Immunol</i> <b>13</b>, 118–132 (2013). https://doi.org/10.1038/nri3383</p><p class="c-bibliographic-information__download-citation u-hide-print"><a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/nri3383?format=refman&flavour=citation">Download citation<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p><ul class="c-bibliographic-information__list" data-test="publication-history"><li class="c-bibliographic-information__list-item"><p>Published<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2013-01-25">25 January 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Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes | Nature Reviews Immunology