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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0900185v1 183/4/2312    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Madan, R. Articles by Karp, C. L. PubMed PubMed Citation Articles by Madan, R. Articles by Karp, C. L.

Nonredundant Roles for B Cell-Derived IL-10 in Immune Counter-Regulation¹

Rajat Madan^*, Filiz Demircik, Sangeetha Surianarayanan^¶, Jessica L. Allen^*, Senad Divanovic^*, Aurelien Trompette^*, Nir Yogev^¶, Yuanyuan Gu^*, Marat Khodoun, David Hildeman, Nicholas Boespflug^*, Mariela B. Fogolin^2,||, Lothar Gröbe^||, Marina Greweling^||, Fred D. Finkelman^,#, Rhonda Cardin, Markus Mohrs^**, Werner Müller^||,, Ari Waisman, Axel Roers^¶ and Christopher L. Karp^3,*

^* Division of Molecular Immunology, Division of Immunobiology, Division of Infectious Diseases, Cincinnati Children’s Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229; First Medical Department, University of Mainz, Mainz, Germany; ^¶ Department of Dermatology, University of Cologne, Cologne, Germany; ^|| Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany; ^# Cincinnati Veteran’s Affairs Medical Center, Cincinnati, OH 45220; ^** Trudeau Institute, Saranac Lake, New York 12983; and Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom

IL-10 plays a central role in restraining the vigor of inflammatory responses, but the critical cellular sources of this counter-regulatory cytokine remain speculative in many disease models. Using a novel IL-10 transcriptional reporter mouse, we found an unexpected predominance of B cells (including plasma cells) among IL-10-expressing cells in peripheral lymphoid tissues at baseline and during diverse models of in vivo immunological challenge. Use of a novel B cell-specific IL-10 knockout mouse revealed that B cell-derived IL-10 nonredundantly decreases virus-specific CD8⁺ T cell responses and plasma cell expansion during murine cytomegalovirus infection and modestly restrains immune activation after challenge with foreign Abs to IgD. In contrast, no role for B cell-derived IL-10 was evident during endotoxemia; however, although B cells dominated lymphoid tissue IL-10 production in this model, myeloid cells were dominant in blood and liver. These data suggest that B cells are an underappreciated source of counter-regulatory IL-10 production in lymphoid tissues, provide a clear rationale for testing the biological role of B cell-derived IL-10 in infectious and inflammatory disease, and underscore the utility of cell type-specific knockouts for mechanistic limning of immune counter-regulation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institute of Allergic and Infectious Diseases Grants AI057992 and AI052099 (to C.L.K. and F.D.F., respectively) and Deutsche Forschungsgemeinschaft Grants SFB 621 and SFB 589 (to W.M. and A.R., respectively).

² Current address: Cell Biology Unit, Institute Pasteur de Montevideo, Uruguay.

³ Address correspondence and reprint requests to Dr. Christopher Karp, Division of Molecular Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati OH 45229. E-mail address: chris.karp{at}chmcc.org

⁴ Abbreviations used in this paper: MCMV, murine cytomegalovirus; eGFP, enhanced GFP; IRES, internal ribosomal entry site; MFI, mean fluorescence intensity.