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Receptor IIB on Dendritic Cells Enforces Peripheral Tolerance by Inhibiting Effector T Cell Responses1
* Department of Medicine and Microbiology, Columbia University College of Physicians and Surgeons, New York, NY 10032; and
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
The uptake of immune complexes by FcRs on APCs augments humoral and cellular responses to exogenous Ag. In this study, CD11c+ dendritic cells are shown to be responsible in vivo for immune complex-triggered priming of T cells. We examine the consequence of Ab-mediated uptake of self Ag by dendritic cells in the rat insulin promoter-membrane OVA model and identify a role for the inhibitory Fc
RIIB in the maintenance of peripheral CD8 T cell tolerance. Effector differentiation of diabetogenic OT-I CD8+ T cells is enhanced in rat insulin promoter-membrane OVA mice lacking FcRIIB, resulting in a high incidence of diabetes. FcRIIB-mediated inhibition of CD8 T cell priming results from suppression of both DC activation and cross-presentation through activating FcRs. Further FcRIIB on DCs inhibited the induction of OVA-specific Th1 effectors, limiting Th1-type differentiation and memory T cell accumulation. In these MHC II-restricted responses, the presence of FcRIIB only modestly affected initial CD4 T cell proliferative responses, suggesting that FcRIIB limited effector cell differentiation primarily by inhibiting DC activation. Thus, FcRIIB can contribute to peripheral tolerance maintenance by inhibiting DC activation alone or by also limiting processing of exogenously acquired Ag.
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 Institutes of Health Grants T32 AI 07525 and T32HL 072739 (to D.D.D. and A.B.) and R01 NCI CA94037, P01AI50514, R01 NIDDK DK70999 and a Pilot and Feasibility Award from the Diabetes and Endocrinology Research Center of Columbia University (Grant DK63608; to R.C.). S.J. is the incumbent of the Pauline Recanati Career Development Chair.
2 Address correspondence and reprint requests to Dr. Raphael Clynes, Columbia University, Department of Microbiology and Medicine, P and S Building, Room 8-510, 630 West 168th Street, Manhattan, NY. E-mail address: rc645{at}columbia.edu
3 Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived DC; DTH, delayed-type hypersensitivity; DTR, diphtheria toxin receptor; IC, immune complex; LN, lymph node; mOVA, membrane OVA; RIP, rat insulin promoter; Tg, transgenic; WT, wild type.
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