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

Aging increases risk for type 2 diabetes (T2D), partly through loss of beta cell identity and function driven by metabolic stress and islet inflammation. While calorie restriction (CR) promotes beta cell longevity in young animals, its impact on cellular aging and inflammatory burden in older individuals is unclear. Using SCENIC regulon and multiomic analyses, we find that aging human alpha cells adopt a coordinated inflammatory phenotype marked by IFN-γ signaling to increase major histocompatibility complex (MHC) class I presentation, and CD8 + T cell recruitment and activation towards islets. In T2D, CD8 + T cells further progress towards an effector memory state. CR reduces alpha cell MHC-I expression while subsequently suppressing CD8 + effector status and accompanied by reduced islet inflammation and immune cell infiltration in mice. Together, these findings highlight an alpha cell–immune signaling axis in aging and T2D that may underlie fibrosis and disease pathophysiology.