Cellular and molecular mechanisms underlying immune tolerance against type 1 diabetes
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Type 1 diabetes (T1D), also known as insulin-dependent diabetes mellitus, is a chronic autoimmune disease caused by the destruction of insulin-producing beta-cells in the pancreatic islets by self-reactive immune cells. About three million Americans have T1D currently and each year there are more than 30,000 new T1D cases in the United States. Hyperglycemia in T1D patients may affect major organs and cause complications including cardiovascular diseases, nerve damage, kidney problems, blindness, and amputation. Unfortunately, there is no cure for T1D and T1D patients have to rely on life-long insulin replacement to maintain blood glucose levels in the normal range. Therefore, immunotherapies which target pathogenic T cells specifically while circumventing broad immune suppression are desired to treat T1D. Our lab has incorporated a mimotope p79 into an Ig molecule, and the resulting Ig-p79 chimera is able to prevent the adoptive transfer of T1D in NOD.scid mice by diabetogenic BDC2.5 T cells. Consequently, these T cells are retained in the spleen and cannot migrate to the pancreas due to diminished expression of the transcription factor T-bet and chemokine receptor CXCR3. Moreover, we found mTOR, a key serine/threonine protein kinase, is the major target of Ig-p79 and T cells undergoing antigen-induced tolerance have an impaired function of mTORC1, but not mTORC2. This mechanism is brought about by antigen presenting cells through upregulation of PD-L1 inhibitory molecules. Under this circumstance, PDL1 on antigen presenting cells interacts specifically with PD-1 on T cells, leading to recruitment of SHP-2 phosphatase to the cytoplasmic tail of PD-1. Active SHP-2 then induces dephosphorylation of phosphatidylinositol-3-kinase protein, which in turn results in the defective activity of mTORC1, diminished expression of CXCR3 and suppression of T1D development. Thus, our findings suggest that drugs that target mTORC1 in diabetogenic T cells would provide an approach to prevent and treat T1D. Moreover, this study also opens a new avenue for antigen presenting cells that express high levels of PD-L1 as means to induce tolerance of pathogenic T cells in T1D patients.