T cell activity in development of Type II Diabetes

Type II diabetes (T2D) is a major health problem worldwide, with special relevance to South East Asia. The disease is associated with chronic inflammation, caused by interplay of immune system and adipose tissue. Perturbed functions of different T cell subsets are important in causing the inflammation in adipose tissue leading to development of T2D. We have discovered that mice deficient in Themis, a newly-discovered protein with critical role in T cell developmental selection, show enhanced development of age and obesity-induced T2D. Themis is only expressed in the T cell lineage, and our laboratory has recently identified Themis as a negative regulator of T cell receptor signal strength through its interaction with tyrosine phosphatase Shp1. The role of Themis in the development of diabetes is novel, and suggests that Themis-deficient mice are a useful model to investigate T cell mediated aspects of T2D induction. We will fully characterize pre-T2D metabolic syndrome and T2D in Themis deficient mice, with detailed investigation of phenotype and cytokine profile of T cell subsets present in visceral adipose tissue from aged and high fat diet fed Themis-deficient mice. We will use adoptive cell transfer to identify T cells involved in the enhanced development of T2D in Themis-deficient mice, and we will analyze expression levels of Themis in T cells in lean and obese adipose tissue. We will characterize phenotype and cytokine profile of Themis-deficient regulatory CD4+ T cell subsets from lymph nodes and adipose tissue, and determine role of gut microbiota in development of Treg functions in metabolic syndrome. As Themis binding partner Shp1 is a critical negative regulator of insulin signalling, we will test T cell intrinsic effects of insulin signalling on Themis-deficient T cell functions. The project will have important implications understanding the role of T cells in development of metabolic syndrome and T2D.