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Igs Cells Recognize Bacteria with Polyreactive Memory B +Iga Circulating Human CD27−IgA+ Memory B Cells Recognize Bacteria with Polyreactive Igs This information is current as Magdalena A. Berkowska, Jean-Nicolas Schickel, Christina of October 2, 2021. Grosserichter-Wagener, Dick de Ridder, Yen Shing Ng, Jacques J. M. van Dongen, Eric Meffre and Menno C. van Zelm J Immunol 2015; 195:1417-1426; Prepublished online 6 July 2015; doi: 10.4049/jimmunol.1402708 Downloaded from http://www.jimmunol.org/content/195/4/1417 Supplementary http://www.jimmunol.org/content/suppl/2015/07/03/jimmunol.140270 http://www.jimmunol.org/ Material 8.DCSupplemental References This article cites 57 articles, 31 of which you can access for free at: http://www.jimmunol.org/content/195/4/1417.full#ref-list-1 Why The JI? Submit online. by guest on October 2, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Circulating Human CD272IgA+ Memory B Cells Recognize Bacteria with Polyreactive Igs Magdalena A. Berkowska,*,1 Jean-Nicolas Schickel,† Christina Grosserichter-Wagener,* Dick de Ridder,‡,2 Yen Shing Ng,† Jacques J. M. van Dongen,* Eric Meffre,†,3 and Menno C. van Zelm*,3 The vast majority of IgA production occurs in mucosal tissue following T cell–dependent and T cell–independent Ag responses. To study the nature of each of these responses, we analyzed the gene-expression and Ig-reactivity profiles of T cell–dependent CD27+ IgA+ and T cell–independent CD272IgA+ circulating memory B cells. Gene-expression profiles of IgA+ subsets were highly similar to each other and to IgG+ memory B cell subsets, with typical upregulation of activation markers and downregulation of inhibitory receptors. However, we identified the mucosa-associated CCR9 and RUNX2 genes to be specifically upregulated in 2 + 2 + CD27 IgA B cells. We also found that CD27 IgA B cells expressed Abs with distinct Ig repertoire and reactivity compared with Downloaded from those from CD27+IgA+ B cells. Indeed, Abs from CD272IgA+ B cells were weakly mutated, often used Igl chain, and were enriched in polyreactive clones recognizing various bacterial species. Hence, T cell–independent IgA responses are likely involved in the maintenance of gut homeostasis through the production of polyreactive mutated IgA Abs with cross-reactive anti- commensal reactivity. The Journal of Immunology, 2015, 195: 1417–1426. he microbiome of the human gastrointestinal tract contains Ig variable domains and class-switch recombination (CSR) from the http://www.jimmunol.org/ large numbers of bacteria (up to 30,000 species) (1). The IgM, for example, to the IgA isotype (8). SHM and CSR are medi- T majority of these bacteria are coated with Igs (2) that are ated by activation-induced cytidine deaminase (AID) (9), which is generated in dynamic responses (3, 4). Indeed, the mucosal sur- upregulated through CD40 signaling following interaction with faces of the intestinal tract, the oral cavity, and lungs are major CD40L on activated CD4+ T cells. Such T cell–dependent (TD) sites of Ab production, mainly the secretory form of IgA (5). responses take place in germinal center reactions in lymphoid tissues. Each B cell carries surface Ig generated through V(D)J re- Alternatively, AID expression can be induced in T cell–independent combination of IgH and Igk and Igl L chain genes during stepwise (TI) B cell responses, which are associated with limited proliferation differentiation in the bone marrow (6, 7). Upon Ag recognition, and affinity maturation to lipid or carbohydrate structures (8, 10–13). by guest on October 2, 2021 these newly generated B cells undergo responses involving affinity TI class-switching toward IgA is well supported by the microenvi- maturation by induction of somatic hypermutations (SHMs) in the ronment of the gut, especially by dendritic cells (DCs) in the GALT. These DCs secrete retinoic acid (RA) that activates circulating B cells a b *Department of Immunology, Erasmus MC, University Medical Center, 3015 CN to induce expression of adhesion molecule 4 7 and chemokine Rotterdam, the Netherlands; †Department of Immunobiology, Yale University School receptor CCR9, which mediate gut homing (14). Upon activation via ‡ of Medicine, New Haven, CT 06511; and The Delft Bioinformatics Lab, Faculty of TLRs, DCs and monocytes secrete BAFF and APRIL, which bind Electrical Engineering, Mathematics, and Computer Science, Delft University of Technology, 2628 CD Delft, the Netherlands TACI on B cells and can induce CD40-independent class-switching b 1Current address: Department of Experimental Immunohematology, Sanquin Re- toward IgA (15–18). In addition, DC-derived TGF- and RA act in search and Landsteiner Laboratory, Amsterdam, the Netherlands. concert with IL-5, IL-6, and IL-10 to induce differentiation of B cells 2Current address: Bioinformatics Group, Wageningen University, Wageningen, the into Ab-secreting plasma cells (14, 18–20). Netherlands. Although ∼25% of intestinal IgA-producing plasmablasts are 3E.M. and M.C.v.Z. are joint senior authors. polyreactive, they show molecular signs of Ag-mediated selection Received for publication October 27, 2014. Accepted for publication June 8, 2015. (21), fitting with Ag-induced production rather than secretion of This work was supported by Grants AI071087, AI082713, AI095848, and AI061093 natural Abs independent of Ag stimulation. It is tempting to spec- from the National Institutes of Health-National Institute of Allergy and Infectious ulate that TI IgA is directed against cell wall components of com- Diseases (to E.M.), as well as by a fellowship from the Ter Meulen Fund–Royal Netherlands Academy of Sciences (to M.A.B.) and fellowships from the Erasmus mensal bacteria to support the formation of a biofilm and to disable University Rotterdam and Erasmus MC (to M.C.v.Z.). their translocation through the epithelial layer (22, 23). This would The microarray data presented in this article have been submitted to ArrayExpress prevent priming of systemic high-affinity TD responses to beneficial under accession numbers E-MEXP-3767 and E-MTAB-3637. gut microbiota. Indeed, MyD88/TRIF double-knockout mice defi- Address correspondence and reprint requests to Dr. Menno C. van Zelm or Dr. Eric Meffre, cient in TI IgA production spontaneously developed systemic Department of Immunology, Erasmus MC, University Medical Center, Wytemaweg 80, responses against gut microbiota (24). 3015 CN Rotterdam, the Netherlands (M.C.v.Z.) or Department of Immunobiology, Yale + University School of Medicine, 300 George Street, New Haven, CT 06511 (E.M.). We recently distinguished two circulating human IgA memory E-mail addresses: [email protected] (M.C.v.Z.) or [email protected] (E.M.). B cell subsets: conventional CD27+IgA+ cells were dependent on 2 The online version of this article contains supplemental material. T cell help, whereas unconventional CD27 IgA+ cells were present Abbreviations used in this article: AID, activation-induced cytidine deaminase; CSR, in CD40L-deficient individuals (25). Moreover, the limited repli- class-switch recombination; DC, dendritic cell; FR, framework region; RA, retinoic cation history of CD272IgA+ memory B cells, their low frequency acid; SHM, somatic hypermutation; TD, T cell dependent; TI, T cell independent. of SHM, and increased IgA2 usage were features reminiscent of + Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 IgA B cells from the intestinal lamina propria (25, 26). We show in www.jimmunol.org/cgi/doi/10.4049/jimmunol.1402708 1418 GENE EXPRESSION AND Ig REACTIVITY OF IgA+ B CELLS 2 this study that both CD27+IgA+ and CD27 IgA+ B cell subsets are (InvivoGen) or sonicated lysates from cultured Enterobacter cloacae (ATCC typical memory B cells, as is evident from their gene-expression 13047), Enterococcus faecalis (ATCC 29212), Escherichia coli,orStrepto- profiles and detailed immunophenotypes. From single-cell–sorted coccus aureus or were obtained by multiple cycles of freezing and thawing + + 2 + lysates from Bacteroides fragilis (ATCC 2528) and Clostridium difficile CD27 IgA and CD27 IgA memory B cells we produced in vitro (ATCC 9689) at a concentration of 1 ng/ml. For indirect immunofluorescence rAbs to assess their reactivity to various Ags and bacterial strains. assays, HEp-2 cell–coated slides (Bion Enterprises) were incubated in We found that a large fraction of CD272IgA+ memory B cells a moist chamber at room temperature with purified rAbs at 50–100 mg/ml, express polyreactive Abs with a unique repertoire and reactivity according to the manufacturer’s instructions. FITC-conjugated goat anti- human IgG was used as detection reagent. toward commensal bacteria, suggesting that these B cells play an important role in maintaining mucosal immunity. Statistical analysis Statistical analyses were performed with the two-tailed Student t test, Materials and Methods Mann–Whitney U test, or x2 test, as indicated in the figure legends. The Cell sorting and gene-expression profiling p values , 0.05 were considered statistically significant. Three naive and six human memory B cell subsets were purified from post- Ficoll mononuclear cells on a FACSAria I cell sorter (BD Biosciences) (25, Results 27). Naive B cells were separated into CD38+CD272IgD+IgM+ transi- 2 Gene-expression profiling of naive and memory B cell subsets tional B cells, CD38dimCD27 IgD+IgM+CD5+ pre–naive B cells, and 2 2 CD38dimCD27 IgD+IgM+CD5 mature naive B cells.
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