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

JT Warshauer, JA Belk, AY Chan, J Wang… - Journal of Experimental …, 2021 - rupress.org
JT Warshauer, JA Belk, AY Chan, J Wang, AR Gupta, Q Shi, N Skartsis, Y Peng, JD Phipps…
Journal of Experimental Medicine, 2021rupress.org
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 …
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.
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