title: Fc gamma receptor IIB on dendritic cells enforces peripheral tolerance by inhibiting effector T cell responses.
abstract: 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 FcgammaRIIB 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 FcgammaRIIB, resulting in a high incidence of diabetes. FcgammaRIIB-mediated inhibition of CD8 T cell priming results from suppression of both DC activation and cross-presentation through activating FcgammaRs. Further FcgammaRIIB 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 FcgammaRIIB only modestly affected initial CD4 T cell proliferative responses, suggesting that FcgammaRIIB limited effector cell differentiation primarily by inhibiting DC activation. Thus, FcgammaRIIB can contribute to peripheral tolerance maintenance by inhibiting DC activation alone or by also limiting processing of exogenously acquired Ag.
authors.affiliation: Department of Medicine and Microbiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Dharmesh D
authors.initials: DD
authors.lastname: Desai
authors.forename: Stephanie O
authors.initials: SO
authors.lastname: Harbers
authors.forename: Marcella
authors.initials: M
authors.lastname: Flores
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Colonna
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Downie
authors.forename: Amy
authors.initials: A
authors.lastname: Bergtold
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
authors.forename: Raphael
authors.initials: R
authors.lastname: Clynes
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism / Q000502:physiology; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D001324:Autoantigens / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045142:Cross-Priming / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D015536:Down-Regulation / Q000276:immunology*; D004705:Endocytosis / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D000936:Antigen-Antibody Complex; D015703:Antigens, CD; D001324:Autoantigens; C080571:Fc gamma receptor IIB; D017452:Receptors, IgG; D010047:Ovalbumin