Autoimmune diseases are common and genetically complex diseases. Recent genome wide association scans (GWAS) have identified multiple new candidate genes that contribute to autoimmune susceptibility. The association of several of these genetic variants with multiple autoimmune diseases indicates that shared disease mechanisms are at play in autoimmunity. Identifying the functional impact of these "common" genes provides researchers with an opportunity to extend their insight into the pathogenic mechanisms which lead to the development of autoimmune diseases in general. In this proposal the research team will address the impact on immune function of one such "common" genetic variant, PTPN2. PTPN2 is associated with the autoimmune diseases type 1 diabetes (T1D), Crohn's disease (CD), and rheumatoid arthritis (RA). PTPN2 is an intracellular phosphatase, which modulates cytokine signal transduction through the Jak/Stat signaling pathways. Signaling via the IL-2 receptor (IL-2R) is a prominent pathway modulated by PTPN2. Preliminary data indicates a link between a disease associated variant of PTPN2 and impaired IL-2R signaling. The IL-2R pathway plays a central role in determining both the magnitude of the adaptive immune response and the maintenance of self tolerance. A loss of IL-2 production or expression of its receptor results in autoimmunity. Given the importance of IL-2 in immune regulation, coupled with the role of PTPN2 in modulating the cellular response to IL-2, one could hypothesize that genetic variants in the PTPN2 gene result in altered IL-2 signal transduction affecting differentiation and function of T cells, predisposing an individual to develop autoimmunity. To address this hypothesis the following specific aims are proposed: SPECIFIC AIM 1: To examine the impact of the autoimmune associated variants in the PTPN2 gene on the expression, splicing, or function of PTPN2, and establish the molecular mechanism by which possession of the variants alter IL-2R signaling. SPECIFC AIM 2: To determine whether the associated variants in PTPN2 affect the differentiation and function of T cells isolated from healthy subjects and individuals diagnosed with T1D. PUBLIC HEALTH RELEVANCE: Recent genetic studies have identified genetic variations that increase an individual's risk of developing autoimmunity, yet we do not know the mechanisms by which these genes lead to autoimmunity. In this grant we will investigate how one recently identified gene, PTPN2, influences the function of the immune system. This gene is associated with multiple autoimmune diseases;so understanding the impact of this gene on the human immune system will help us understand the pathways which lead to autoimmunity.