DESCRIPTION (provided by applicant): Obesity has reached epidemic proportions, affecting more than one third of Americans with almost 10 percent of Americans affected by type 2 diabetes (T2D). T2D is considered a metabolic disease that is largely induced by obesity, while type 1 diabetes (T1D) is an immune-mediated disease. However, multiple hallmarks of T1D can be detected in some T2D patients, suggesting that an islet-specific autoimmune component could be present in obesity and/or T2D. This application will investigate the role of islet-infiltrating lymphocytes in obesity with the goal of understanding how breaks in lymphocyte tolerance lead to altered beta function. We discovered that T cells and B cells infiltrate the isles in the high fat fed, diet induced obesity model which develops insulin resistance resulting in pre-T2D. These islet-infiltrating lymphocytes had a high percentage of regulatory T cells. However, virtually nothing is known about the function of lymphocytes within the islets during obesity. The human disease relevance of our finding is supported by a study that found lymphocyte infiltration in the islets of T2D patients. Also present in obesity is systemic inflammation that i characterized by circulating inflammatory cytokines and local islet and adipose inflammation that is promoted by the accumulation of classically activated (M1) mononuclear phagocytes. M1 mononuclear phagocytes promote beta cell dysfunction and death, while alternatively activated (M2) mononuclear phagocytes are associated with normal islets and islet repair. In obesity, there is also evidence to suggest that there are lymphocytes that are autoreactive for adipose tissue antigens. If obesity-induced inflammation can induce a break in immunological tolerance to adipose antigens can it also induce a break in tolerance to islet antigens? We hypothesize that in obesity, islet-infiltrating effector lymphocytes are islet-specific and promote beta cell dysfunction and death, in part through activation of M1 mononuclear phagocytes; however, local regulatory lymphocytes control M1 mononuclear phagocyte- mediated inflammation to maintain beta cell function. To test this hypothesis we propose the following aims: (1) to determine if in obesity, islet-infiltrating T cells and B cells are islet-antigen specific; (2) to determine the efect of islet-infiltrating lymphocyte subsets on beta cell death and dysfunction; and (3) to determine how islet- infiltrating lymphocyte subsets affect the number, phenotype and function of mononuclear phagocytes in the islets. Understanding the function of islet-infiltrating lymphocytes in obesity could change our understanding of how obesity alters lymphocyte tolerance leading to susceptibility to both T1D and T2D, thereby revealing new areas of therapeutic intervention to support beta cell function and survival in both forms of diabetes.

PUBLIC HEALTH RELEVANCE: Obesity has reached epidemic proportions in the US and worldwide, affecting more than one third of Americans. In obesity, immune cells contribute to insulin resistance and dysfunction of the insulin-secreting beta cells of the pancreatic islets, ye almost nothing is known about the role of pancreatic islet-infiltrating lymphocytes (a type of immune cell) in beta cell function and survival or modulation of the local immune response. As a result, the goals of this application are to determine the role of islet-infiltrating lymphocytes i beta cell function and survival as well as to understand how islet-infiltrating lymphocytes modulate the pathogenic effects of other immune cells in the islets during obesity and pre-type 2 diabetes.