A human mutation in STAT3 promotes type 1 diabetes through a defect in CD8+ T cell tolerance

Abstract Naturally occurring cases of monogenic type 1 diabetes (T1D) provide rare opportunities to establish direct mechanisms that cause this complex autoimmune disease. A recently identified de novo germline gain-of-function (GOF) mutation in the transcriptional regulator signal transducer and activator of transcription 3 (STAT3) was shown to cause neonatal T1D at birth. To investigate the role of STAT3 hyperactivity in T1D, we engineered a novel knock-in (KI) mouse incorporating this highly diabetogenic human mutation (K392R) in the STAT3 gene. These mice developed accelerated diabetes with severe insulitis and insulin autoantibodies, thereby recapitulating the human autoimmune diabetes phenotype. Paired T cell receptor (TCR) and transcriptome (RNA) sequencing in single cells revealed that STAT3-GOF drives the proliferation and clonal expansion of highly cytotoxic effector CD8+ T cells that are resistant to terminal exhaustion. Single-cell ATAC-seq showed that these effector T cells are epigenetically distinct and revealed differential chromatin architecture induced by STAT3-GOF. Analysis of islet TCR clonotypes revealed an effector CD8+ T cell reacting against the known antigen IGRP, and STAT3-GOF in an IGRP-reactive TCR transgenic model demonstrated that STAT3-GOF intrinsic to CD8+ T cells is sufficient to accelerate diabetes onset. Taken together, these findings reveal a diabetogenic CD8+ T cell response that is restrained in the presence of normal STAT3 activity and drives diabetes pathogenesis.