Abstract EN:

Several mechanisms of peripheral self-tolerance, including CD4+ CD25+ Foxp3+ regulatory T cells (Tregs), cross-presentation by dendritic cells (DCs) and the newly identified direct presentation of antigen by lymph node (LN) stromal cells, contribute to protecting our bodies and animals from self-damaging autoimmune diseases. We first sought to determine the relative contribution of antigen-specific CD8 and CD4 T cells to intestinal autoimmunity. To this end, we studied autoimmune targeting of an ectopic antigen expressed by enteric glial cells, in transgenic mouse models. We found that direct presentation of antigen by LN stromal cells caused the activation induced cell death of specific CD8 T cells. In contrast, conventional CD4 T cells were not affected by this mechanism of tolerance and their targeting of enteric glial cells produced lethal intestinal autoimmunity. Thus, we conclude that in our mouse model, this novel mechanism of peripheral tolerance preferentially protects against CD8 T cell intestinal autoimmunity. Furthermore, we have established a new model of antigen-specific CD4 T cell-mediated small intestine autoimmunity. To determine the relative contribution of Tregs, DCs and LN stromal cells for protection against autoimmunity, we sought conditions that make adoptively transferred naïve conventional CD8 T cells autoaggressive. Depletion of Treg cells, non-specific activation of the T cells through their lymphopenic expansion, and inhibition of TGF-beta receptor signaling in T cells achieved autoimmunity. The CD8 T cells caused multi-organ autoimmunity, but the intestine was not affected. Since insensitivity to TGF-beta rendered the T cells resistant to deletion through cross-presentation but not direct presentation of antigen, we conclude that the former was the critical mechanism determining the outcome of the immune response. Furthermore, these observations leave the possibility open that direct presentation by LN stromal cells preferentially protects the intestine against CD8 T cell attack, although other mechanisms of mucosal tolerance may be also involved. Altogether, these results provide new insights into the mechanisms of peripheral CD8 T cell tolerance, and tissue specific autoimmunity. A thorough understanding of these events is necessary to allow effective therapeutic intervention in autoimmunity and cancer.