Circulating CD4⁺ T_EMRA and CD4⁺ CD28^- T cells and incident diabetes among persons with and without HIV

Objective: A higher proportion of circulating memory CD4⁺ T cells is associated with prevalent diabetes mellitus in persons with HIV (PWH) and HIV-negative persons. We assessed whether circulating T-cell subsets could also identify individuals who will subsequently develop diabetes. Design: This is a longitudinal follow-up study of PWH and similar HIV-negative individuals from the Veterans Aging Cohort Study who provided peripheral mononuclear blood cells between 2005 and 2007. Methods: We quantified T-cell subsets using flow cytometry and functional assays to identify CD4⁺ and CD8⁺ naive, activated, senescent, memory (central, effector, and effector RA⁺), and T_H1, T_H2, and T_H17-phenotype cells. The occurrence of an incident diabetes diagnosis (i.e. after baseline blood draw) was adjudicated by a two-physician chart review. Cox proportional hazards models adjusted for traditional risk factors, cytomegalovirus serostatus, and plasma inflammatory biomarkers assessed the relationship between T-cell subsets and incident diabetes. Results: One thousand, eight hundred and thirty-seven participants (1259 PWH) without diabetes at baseline were included; 69% were black, 95% were men, and median follow-up was 8.6 years. Higher baseline frequencies of CD4⁺ T effector memory RA⁺ (T_EMRA) cells defined as CD45RA⁺ CD27^- (P = 0.04) and senescent T cells defined as CD4⁺ CD28^- (P = 0.04) were associated with incident diabetes in PWH only. Conclusions: Higher frequencies of CD4⁺ T_EMRA and CD4⁺ CD28^- T cells were associated with incident diabetes in PWH only after adjustment for other factors. Additional studies are necessary to assess whether these cells act in blood via inflammatory mediators or reflect T-cell populations in metabolically active tissues.