| First Author | Warshauer JT | Year | 2021 |
| Journal | J Exp Med | Volume | 218 |
| Issue | 8 | PubMed ID | 34115115 |
| Mgi Jnum | J:342716 | Mgi Id | MGI:6755009 |
| Doi | 10.1084/jem.20210759 | Citation | Warshauer JT, et al. (2021) A human mutation in STAT3 promotes type 1 diabetes through a defect in CD8+ T cell tolerance. J Exp Med 218(8) |
| abstractText | Naturally occurring cases of monogenic type 1 diabetes (T1D) help establish direct mechanisms driving this complex autoimmune disease. A recently identified de novo germline gain-of-function (GOF) mutation in the transcriptional regulator STAT3 was found to cause neonatal T1D. We engineered a novel knock-in mouse incorporating this highly diabetogenic human STAT3 mutation (K392R) and found that these mice recapitulated the human autoimmune diabetes phenotype. Paired single-cell TCR and RNA sequencing revealed that STAT3-GOF drives proliferation and clonal expansion of effector CD8+ cells that resist terminal exhaustion. Single-cell ATAC-seq showed that these effector T cells are epigenetically distinct and have differential chromatin architecture induced by STAT3-GOF. Analysis of islet TCR clonotypes revealed a CD8+ cell reacting against known antigen IGRP, and STAT3-GOF in an IGRP-reactive TCR transgenic model demonstrated that STAT3-GOF intrinsic to CD8+ cells is sufficient to accelerate diabetes onset. Altogether, these findings reveal a diabetogenic CD8+ T cell response that is restrained in the presence of normal STAT3 activity and drives diabetes pathogenesis. |
