Pancreatic α cells function as MHC class II-dependent antigen-presenting cells in type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of pancreatic β cells, in which antigen presentation is essential. Although professional antigen-presenting cells initiate autoreactive T cell responses, whether endocrine cells contribute to antigen presentation within inflamed islets remains unclear. Here, we show that pancreatic α cells acquire major histocompatibility complex (MHC) class II (MHC-II)-dependent antigen-presenting capacity during T1D progression. Reanalysis of single-cell RNA sequencing datasets from nonobese diabetic (NOD) mice and human T1D islets revealed progressive up-regulation of MHC-II associated genes in α cells. Immunostaining validated the increased of MHC-II level both in NOD mice and patients with T1D. Mechanistically, inflammatory cytokines activated the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in α cells, leading to JAK-STAT-dependent MHC-II induction. Functionally, activated α cells internalized, processed, and presented exogenous antigens, acquired expression of costimulatory molecules, and promoted antigen-specific CD4⁺ T cell activation. These findings identify pancreatic α cells as nonprofessional antigen-presenting cells and expand the current understanding of antigen presentation in autoimmune diabetes.