Adipose tissue contains a network of leukocytes that respond to obesity by generating proinflammatory signals that contribute to metabolic disease. At the same time, there is strong evidence that many healthy immune responses are impaired in obesity and contribute to an increased severity of illness to many diseases that include respiratory viruses. We currently do not have a clear understanding of the mechanisms behind this dichotomy. Addressing this gap can reveal mechanisms by which a hyperactive immune system can be restrained to improve insulin resistance and can also identify mechanisms by which normal immune responses can be preserved to improve health in people with obesity. This proposal seeks to understand immune responses in adipose tissue by focusing on the mechanisms by which the innate and adaptive components of the adipose tissue immune system interact in mice and humans. Our central hypothesis is that the chronic pro-inflammatory environment generated by obesity triggers T cell and myeloid exhaustion. We further posit that the diversity of adipose tissue macrophages (ATM) and dendritic cells (ATDC) shape adipose tissue T cell responses that impair healthy resolution of adipose tissue inflammation. The premise for this hypothesis is based on the published work generated in the last grant cycle, as well as preliminary data demonstrating a impaired T cell activation capacity in obese adipose tissue from mice and humans associated with decrease diversity of T cells in obese humans and enrichment for novel subtypes of ATDC. Our approach will identify the mechanisms by which adipose tissue T cells become exhausted with dietary obesity by testing the hypothesis that the induction of T cell exhaustion profiles requires differential APC signals and the induction of BTLA receptors in T cells. We will also evaluate the hypothesis that endogenous glucocorticoids alter the ability of ATMs and ATDC to activate T cells in a way that promotes exhaustion. Completing these aims further advance the understanding of the cell-cell communication networks that are generated in adipose tissue and how they contribute to metabolic disease.