{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T12:21:26Z","timestamp":1776687686841,"version":"3.51.2"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013799","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000}}],"reference-count":68,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI176124, AI175174"],"award-info":[{"award-number":["AI176124, AI175174"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases","award":["PE00000007, INF-ACT"],"award-info":[{"award-number":["PE00000007, INF-ACT"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"\n Francisella tularensis<\/jats:italic>\n (\n Ft<\/jats:italic>\n ), a Gram-negative bacterium that causes tularemia, possesses a non-inflammatory atypical LPS (LPS\n \n Ft<\/jats:italic>\n <\/jats:sub>\n ) that is highly immunogenic through unknown mechanism. We previously showed that immunization with LPS\n \n Ft<\/jats:italic>\n <\/jats:sub>\n , a type 2 T-independent (TI) antigen, elicits protective LPS\n \n Ft<\/jats:italic>\n <\/jats:sub>\n -specific IgM (IgM\n \n Ft<\/jats:italic>\n <\/jats:sub>\n ) and IgG3\n \n Ft<\/jats:italic>\n <\/jats:sub>\n by B1 cells in a mechanism dependent on the IL-5 produced by innate lymphoid cells type 2 (ILC2). Here, we examined the role of complement in the B1 cells\u2019 response against LPS\n \n Ft<\/jats:italic>\n <\/jats:sub>\n .\n C3<\/jats:italic>\n -\/-<\/jats:sup>\n ,\n C1q<\/jats:italic>\n -\/-<\/jats:sup>\n and\n C4<\/jats:italic>\n -\/-<\/jats:sup>\n mice immunized with LPS\n \n Ft<\/jats:italic>\n <\/jats:sub>\n failed to produce IgM\n \n Ft<\/jats:italic>\n <\/jats:sub>\n and IgG3\n \n Ft<\/jats:italic>\n <\/jats:sub>\n . In contrast, the response of\n Cfb<\/jats:italic>\n -\/-<\/jats:sup>\n and\n Mbl1\/Mbl2<\/jats:italic>\n -\/-<\/jats:sup>\n mice was comparable to that of WT mice. Thus, activation of the classical complement cascade, but not the alternative or the Mannose Binding Lectin pathway, is required for activation of B1 cells and production of LPS\n \n Ft<\/jats:italic>\n <\/jats:sub>\n -specific antibodies. Complement activation generates the C3d fragment, which opsonizes antigens for recognition by complement receptor-2 (CR2), and the C3a and C5a anaphylatoxins. Our results show that C3d opsonized LPS\n \n Ft<\/jats:italic>\n <\/jats:sub>\n and that the response to immunization was dependent on CR2 expression by B1 cells. Importantly, the response to LPS\n \n Ft<\/jats:italic>\n <\/jats:sub>\n immunization was also drastically decreased in\n C3ar1<\/jats:italic>\n -\/-<\/jats:sup>\n , but not in\n C5ar1<\/jats:italic>\n -\/-<\/jats:sup>\n mice. C3a induced IL-5 in ILC2, which supported B1 cells activation. Decreased antibody production in\n C3ar1<\/jats:italic>\n -\/-<\/jats:sup>\n and\n Cr2<\/jats:italic>\n \n -\/-<\/jats:italic>\n <\/jats:sup>\n mice correlated with increased susceptibility to tularemia. Together, these results demonstrate that the high immunogenicity of LPS\n \n Ft<\/jats:italic>\n <\/jats:sub>\n depends on two effector mechanisms triggered by activation of the classical complement pathway: 1) tagging of LPS\n \n Ft<\/jats:italic>\n <\/jats:sub>\n with C3d fragment, leading to its interaction with CR2 expressed by B1 cells; 2) production of the anaphylatoxin C3a that stimulated IL-5 secretion by ILC2. Our study increases our understanding of the B1 cells\u2019 response to TI-2 antigens and identifies two complement effector mechanisms that can be harnessed for therapeutic interventions.\n <\/jats:p>","DOI":"10.1371\/journal.ppat.1013799","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T18:39:40Z","timestamp":1765996780000},"page":"e1013799","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Activation of B1 B cells by F. tularensis atypical LPS depends on classical complement and C3a"],"prefix":"10.1371","volume":"21","author":[{"given":"Guilherme","family":"Melo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos Henrique D.","family":"Barbosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Magrini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecilia","family":"Garlanda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1181-0717","authenticated-orcid":true,"given":"Fabio","family":"Re","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"issue":"1","key":"ppat.1013799.ref001","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/imr.12865","article-title":"Signals 1, 2 and B cell fate or: Where, when and for how long?","volume":"296","author":"JS Turner","year":"2020","journal-title":"Immunol Rev"},{"issue":"5489","key":"ppat.1013799.ref002","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1126\/science.290.5489.89","article-title":"T-Independent immune response: new aspects of B cell biology","volume":"290","author":"S Fagarasan","year":"2000","journal-title":"Science"},{"issue":"1","key":"ppat.1013799.ref003","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1111\/imr.12754","article-title":"The continuing story of T-cell independent antibodies","volume":"288","author":"D Allman","year":"2019","journal-title":"Immunol Rev"},{"issue":"3","key":"ppat.1013799.ref004","doi-asserted-by":"crossref","first-page":"833","DOI":"10.4049\/jimmunol.146.3.833","article-title":"Dextran-conjugated anti-Ig antibodies as a model for T cell-independent type 2 antigen-mediated stimulation of Ig secretion in vitro. 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Lymphokine dependence","volume":"146","author":"LM Pe\u00e7anha","year":"1991","journal-title":"J Immunol"},{"key":"ppat.1013799.ref005","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1034\/j.1600-065X.2000.00607.x","article-title":"B-cell activation by T-cell-independent type 2 antigens as an integral part of the humoral immune response to pathogenic microorganisms","volume":"176","author":"Q Vos","year":"2000","journal-title":"Immunol Rev"},{"key":"ppat.1013799.ref006","doi-asserted-by":"crossref","first-page":"324","DOI":"10.3389\/fimmu.2016.00324","article-title":"B-1 Cell Heterogeneity and the Regulation of Natural and Antigen-Induced IgM Production","volume":"7","author":"N Baumgarth","year":"2016","journal-title":"Front Immunol"},{"key":"ppat.1013799.ref007","doi-asserted-by":"crossref","first-page":"535","DOI":"10.3389\/fimmu.2014.00535","article-title":"B1b cells recognize protective antigens after natural infection and vaccination","volume":"5","author":"AF Cunningham","year":"2014","journal-title":"Front Immunol"},{"issue":"5","key":"ppat.1013799.ref008","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1002\/JLB.3RI0519-161R","article-title":"Secreted IgM: New tricks for an old molecule","volume":"106","author":"R Blandino","year":"2019","journal-title":"J Leukoc Biol"},{"key":"ppat.1013799.ref009","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.coi.2018.12.001","article-title":"B-1 cell responses to infections","volume":"57","author":"FL Smith","year":"2019","journal-title":"Curr Opin Immunol"},{"key":"ppat.1013799.ref010","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.molimm.2004.03.017","article-title":"The complement system in B cell regulation","volume":"41","author":"MC Carroll","year":"2004","journal-title":"Mol Immunol"},{"issue":"2","key":"ppat.1013799.ref011","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.immuni.2012.08.002","article-title":"Regulation of humoral immunity by complement","volume":"37","author":"MC Carroll","year":"2012","journal-title":"Immunity"},{"key":"ppat.1013799.ref012","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S0065-2776(08)60908-6","article-title":"The role of complement in B cell activation and tolerance","volume":"74","author":"MC Carroll","year":"2000","journal-title":"Adv Immunol"},{"issue":"5247","key":"ppat.1013799.ref013","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1126\/science.271.5247.348","article-title":"C3d of complement as a molecular adjuvant: bridging innate and acquired immunity","volume":"271","author":"PW Dempsey","year":"1996","journal-title":"Science"},{"issue":"4","key":"ppat.1013799.ref014","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/s00281-004-0186-y","article-title":"Complement receptors and the shaping of the natural antibody repertoire","volume":"26","author":"VM Holers","year":"2005","journal-title":"Springer Semin Immunopathol"},{"key":"ppat.1013799.ref015","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1385\/IR:36:1:197","article-title":"Complement-mediated activation of the adaptive immune responses: role of C3d in linking the innate and adaptive immunity","volume":"36","author":"FR Toapanta","year":"2006","journal-title":"Immunol Res"},{"issue":"1","key":"ppat.1013799.ref016","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1046\/j.1365-2249.2002.01953.x","article-title":"The dual function of the splenic marginal zone: essential for initiation of anti-TI-2 responses but also vital in the general first-line defense against blood-borne antigens","volume":"130","author":"A Zandvoort","year":"2002","journal-title":"Clin Exp Immunol"},{"issue":"3","key":"ppat.1013799.ref017","doi-asserted-by":"crossref","first-page":"236","DOI":"10.2174\/187152809788681038","article-title":"The role of anaphylatoxins C3a and C5a in regulating innate and adaptive immune responses","volume":"8","author":"Q Peng","year":"2009","journal-title":"Inflamm Allergy Drug Targets"},{"issue":"1","key":"ppat.1013799.ref018","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1111\/imr.12473","article-title":"Old dogs-new tricks: immunoregulatory properties of C3 and C5 cleavage fragments","volume":"274","author":"A Verschoor","year":"2016","journal-title":"Immunol Rev"},{"issue":"3","key":"ppat.1013799.ref019","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.4049\/jimmunol.130.3.1257","article-title":"Anaphylatoxin-mediated regulation of the immune response. 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