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Type 1 diabetes (T1D) results from T cell–mediated destruction of insulin-producing β-cells. Insulin represents a key self-antigen in disease pathogenesis, as recent studies identified proinsulin-responding T cells from inflamed pancreatic islets of organ donors with recent-onset T1D. These cells respond to an insulin B-chain (InsB) epitope presented by the HLA-DQ8 molecule associated with high T1D risk. Understanding insulin-specific T-cell frequency and phenotype in peripheral blood is now critical. We constructed fluorescent InsB_10–23:DQ8 tetramers, stained peripheral blood lymphocytes directly ex vivo, and show DQ8⁺ patients with T1D have increased tetramer⁺ CD4⁺ T cells compared with HLA-matched control subjects without diabetes. Patients with a shorter disease duration had higher frequencies of insulin-reactive CD4⁺ T cells, with most of these cells being antigen experienced. We also demonstrate …