REGULATORY CD4-CD8- T CELLS PREVENT AUTOIMMUNE DIABETES (143.4)

Abstract

Abstract Regulatory T cells show great potential for use in cellular therapy. In particular, CD4-CD8- (DN) T cells, which compose 1 to 3% of total T lymphocytes, exhibit prominent antigen-specific immune tolerance properties in models of allografts and xenografts, as well as in an induced model of autoimmune diabetes. Here, we evaluate the immunoregulatory properties of DN T cells in the autoimmune-prone NOD genetic background. Using the 3A9 TCR transgenic mice, we demonstrate that DN T cells from both autoimmune-resistant and -prone mice are equally effective at eliminating potentially autoreactive B cells in vitro. However, autoimmune-prone mice carry at least three fold fewer DN T cells than autoimmune-resistant mice, in both TCR transgenic and non-transgenic setting. Interestingly, a single transfer of DN T cells is sufficient to prevent autoimmune diabetes onset in autoimmune-prone mice. These results suggest that increasing DN T cell number is sufficient to confer protection from autoimmune diabetes onset. Further functional and genetic characterization of DN T cells in NOD mice highlighted a potential role for both CD172a and IL-10 in the regulation of DN T cell homeostasis. Importantly, genetic polymorphisms in both CD172a and IL-10 are associated with diabetes susceptibility in humans. Taken together, our results strongly suggest a role for DN T cell in peripheral tolerance and the association of genetic defects in DN T cell homeostasis with the development of diabetes.