The Role of Adipose-Resident T Cells in HIV-Associated Glucose Intolerance

点击翻译按钮获取中文摘要

Project Summary HIV-infected (HIV+) persons can survive decades on antiretroviral therapy, but this success is accompanied by a disproportionate burden of metabolic disease, including type 2 diabetes, in the HIV population. We hypothesize that the accumulation of chronically activated T cells in the adipose tissue of HIV+ persons is a central mechanism promoting local macrophage activation, impaired adipocyte function, and the development of HIV-associated glucose intolerance. This hypothesis is supported by our preliminary data showing 1.) a higher percentage of circulating memory CD4+ T cells in HIV+ persons is associated with insulin resistance and incident diabetes. 2.) Adipose tissue biopsies from HIV+ persons are enriched for activated CD8+ T cells compared to blood, and there is a strong correlation between the percentage of adipose-resident and circulating memory CD4+ T cells. 3.) In our murine model of obesity and insulin resistance, we found an association between adipose-resident CD8+ T cell density and T cell receptor oligoclonality, suggesting the expansion of CD8+ T cells in adipose tissue may represent an antigen-driven process Prior studies of immune activation and HIV-associated metabolic disease have only measured circulating T cell subsets. In contrast, our study will recruit a longitudinal cohort of HIV+ patients on antiretroviral therapy ranging from insulin sensitive to overtly diabetic, in addition to HIV-negative diabetic controls, to identify potential mechanistic linkages between adipose-resident T cell cytokine signaling, adipose tissue inflammation, and glucose intolerance in HIV+ persons. Our three aims will determine whether circulating blood T cell subsets are reflective of adipose-resident subsets in HIV+ persons (Aim 1), whether activated adipose-resident T cells contribute to macrophage activation, adipocyte dysfunction, and glucose intolerance (Aim 2), and whether greater adipose-resident CD8+ T cell receptor oligoclonality is correlated with metabolic dysfunction (Aim 3), which may indicate the development of HIV-associated diabetes has an antigen-driven component. This study will: 1.) clarify the role of chronic, HIV-related T cell activation in the development of glucose intolerance, 2.) assess whether the cytokine signaling profiles of adipose-resident activated, memory, and other T cell types differ from what is already known about circulating T cells, 3.) clarify the metabolic consequences of adipose tissue as a reservoir for latently HIV-infected CD4+ T cells, 4.) identify potential immunologic therapeutics targets for metabolic disease and HIV cure research, and 5.) assess whether adipose-resident CD8+ T cell oligoclonal expansion accompanies adipocyte dysfunction and glucose intolerance, and should be explored further to identify epitopes potentially contributing to HIV-associated metabolic disease. This study may also provide further insight into the role of T cells in the development of glucose intolerance in HIV-negative patients.