RESUMO
Recently, it has become clear that dendritic cells (DCs) are essential for the priming of T cell responses. However, their role in the maintenance of peripheral T cell tolerance remains largely undefined. Herein, an antigen-presenting cell (APC) transfer system was devised and applied to experimental allergic encephalomyelitis (EAE), to evaluate the contribution that DCs play in peripheral T cell tolerance. The CD8alpha(-)CD4(+) subset, a minor population among splenic DCs, was found to mediate both tolerance and bystander suppression against diverse T cell specificities. Aggregated (agg) Ig-myelin oligodendrocyte glycoprotein (MOG), an Ig chimera carrying the MOG 35-55 peptide, binds and cross-links FcgammaR on APC leading to efficient peptide presentation and interleukin (IL)-10 production. Furthermore, administration of agg Ig-MOG into diseased mice induces relief from clinical EAE involving multiple epitopes. Such recovery could not occur in FcgammaR-deficient mice where both uptake of Ig-MOG and IL-10 production are compromised. However, reconstitution of these mice with DC populations incorporating the CD8alpha(-)CD4(+) subset restored Ig-MOG-mediated reversal of EAE. Transfer of CD8alpha(+) or even CD8alpha(-)CD4(-) DCs had no effect on the disease. These findings strongly implicate DCs in peripheral tolerance and emphasize their functional potency, as a small population of DCs was able to support effective suppression of autoimmunity.
Assuntos
Autoimunidade , Células Dendríticas/imunologia , Tolerância a Antígenos Próprios , Linfócitos T/imunologia , Sequência de Aminoácidos , Animais , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/prevenção & controle , Glicoproteínas/genética , Glicoproteínas/imunologia , Interleucina-10/biossíntese , Lipoproteínas/genética , Lipoproteínas/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Receptores de IgG/deficiência , Receptores de IgG/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Subpopulações de Linfócitos T/imunologiaRESUMO
IFN-gamma is well known as the signature cytokine of CD4+ T helper 1, CD8+, and natural killer cells, but recent studies demonstrate that antigen-presenting cells, in particular dendritic cells (DCs), are another potent source for this proinflammatory cytokine. T-bet, a transcription factor that controls IFN-gamma expression in CD4+ T cells, was reported recently to be expressed in human monocytes and myeloid DCs. In this study we investigate the role of T-bet in this important cell type. The development, differentiation, and activation of bone marrow and splenic DCs were unimpaired in mice lacking T-bet. However, T-bet was essential for the optimal production of IFN-gamma by both CD8alpha+ and CD8alpha- DCs. T-bet-deficient DCs were significantly impaired in their capacity to secrete IFN-gamma after both stimulation with IL-12 alone or in combination with IL-18. Further, T-bet-/- DCs were impaired in their ability to activate the T helper 1 program of adoptively transferred antigen-specific T cells in vivo. The rapid up-regulation of T-bet by IFN-gamma in DCs coupled with a function for DC-derived IFN-gamma in T cell activation may constitute a positive feedback loop to maximize type 1 immunity.