Alpha cell MHC-I expression recruits cytotoxic CD8 ⁺ T cells during human aging and type 2 diabetes

Aging is a major risk factor for type 2 diabetes (T2D), driven in part by loss of beta cell identity and function due to stress and islet inflammation. Calorie restriction (CR) improves metabolic health by promoting beta cell longevity in young animals. It remains unknown whether CR reverses cellular aging and dampens islet inflammation in aged animals. We show that aging alpha cells have an active inflammatory phenotype with increased IFNα/γ signaling that activates major histocompatibility complex (MHC-I) expression to promote CD8 ⁺ T-cell accumulation in mouse and human islets. During human T2D, aging islet-resident CD8 ⁺ T cells transition from memory states to activated effector phenotypes. Moreover, CR dampens alpha cell MHC-I expression to suppress CD8 ⁺ cytotoxicity, which is sufficient to prevent islet inflammation and fibrosis in mice and non-human primates. Together, these findings highlight alpha cell MHC-I within the islet endocrine–immune axis in aging that may underlie fibrosis and disease development.