Antigen-specific tolerance of diabetogenic T cells inhibits mTOR expression and function (THER6P.854)

Abstract

Abstract In prior studies we have shown that antigen-induced tolerance of diabetogenic Th1 cells leads to diminished expression of the transcription factor T-bet and downregulation of the chemokine receptor CXCR3. Consequently, the cells are retained in the spleen, can not traffic to the pancreas, and the mice are resistant to type 1 diabetes (T1D). Investigation of the molecular events underlying this form of Th1 tolerance indicates that expression of the mammalian target of rapamycin (mTOR), a conserved serine/threonine kinase involved in regulation of cell metabolism, is inhibited and its function is impaired. Specifically, phosphorylation of the ribosomal protein S6 kinase, a target of mTOR complex 1 (mTORC1) is decreased whereas mTORC2-dependent phosphorylation of AKTS473 is unaffected. In contrast, overexpression of mTOR or its positive regulator, Akt, by viral transduction nullifies antigen-induced tolerance and accelerates progression of T1D. Thus, mTOR plays a major role in the regulation of T cell activation and provides a useful target for modulation self-reactive T cells and suppression of autoimmune or type 1 diabetes.