Induced Organ-Specific T Regulatory (Treg) Cells Prevent Autoimmunity by Reducing the Ability of Dendritic Cells (DC) to Present Self-Antigen. (131.4)

Abstract

Abstract Foxp3− T cells can be converted to Foxp3+ T reg cells by T cell stimulation in the presence of TGFb. TGFb-induced Tregs (iTregs) have been shown to prevent the induction of autoimmunity although little is known about their mechanism of action in vivo. Here we demonstrate that naïve CD4+Foxp3− T cells specific for the gastric parietal cell antigen, H+/K+ ATPase, can be converted to Foxp3+ T regulatory cells following TCR activation in the presence of TGFb. The iTregs were anergic to TCR stimulation, failed to produce effector cytokines, and were suppressive in vitro. When co-transferred with disease inducing CD4+ T cells, the iTreg were long lived in vivo and were able to prevent organ-specific autoimmunity. iTregs prevented the initial activation and expansion of autoreactive T cells in response to H+/K+ ATPase presented by DC in the gastric lymph node. Gastric lymph node DC from animals that were treated with iTreg had a markedly reduced ability to stimulate H+/K+ ATPase-specific T cells in vitro. When stimulated by peptide in vitro, iTregs mediated the downregulation of the costimulatory molecules CD80 and CD86, but not MHC class II or CD40, on the surface of DC. These data demonstrate that the autoantigen presenting DC is the major target for Treg mediated suppression in vivo, and raise the possibility of using TGFb to generate large numbers of organ-specific Tregs to prevent and possibly treat autoimmunity.