The Role of CX3CR1+ GPR56+ CD57+ T Cells in Metabolic Disease

People living with HIV (PLWH) on antiretroviral therapy (ART) experience improved longevity and reduced AIDS-related mortality. However, they have a higher incidence of cardiometabolic diseases, such as diabetes and atherosclerotic cardiovascular disease, compared to people without HIV (PWoH). Persistent systemic inflammation despite ART and the interplay of traditional risk factors with HIV-related inflammation may drive this elevated risk. Cytotoxic CD4+ T cells are significantly more abundant in PLWH than in PWoH and correlate with diabetes and cardiovascular disease. These cells co-express CX3CR1, GPR56, and CD57 (CGC+ CD4+ T cells). CX3CR1hi T cells are implicated in intravascular homeostasis and glucose metabolism, suggesting their involvement in diabetes pathogenesis. Our overall hypothesis is that in PLWH, CGC+ CD4+ T cells are recruited to the liver and adipose tissue, promoting insulin resistance under high-calorie diets. To investigate, we adoptively transferred PBMCs from PLWH and PWoH into immune-suppressed mice lacking B and T cells and MHCI/MHCII (NSG mice). Mice on a high-fat diet (HFD) receiving PBMCs from PLWH gained the most weight, correlating with donor CGC+ CD4+ T cell proportions. Immunohistochemistry revealed human T cells localized to the perivascular regions of the liver and visceral adipose tissue. Based on these findings, we propose two aims. Aim 1 will test whether human CGC+ CD4+ T cells from PLWH drive endothelial dysfunction, additional immune recruitment, and metabolic disease in HFD-fed mice. Aim 2 will determine whether CX3CR1+ T cells are recruited to perivascular spaces by endothelial CX3CL1 in NSG mice. Targeting CX3CR1 with existing inhibitors could offer a new treatment option to reduce the recruitment of CX3CR1+ T cells into tissue and dampen the role of chronic inflammation in metabolic disease. The results from these studies will support future R01 grant applications to develop this therapeutic approach further.