Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 218, Issue 8, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20210759
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Funding
- National Institutes of Health Medical Scientist Training Program [2T32DK007418-36A1]
- Endocrine Fellows Foundation
- National Institutes of Health Diabetes Re-search Center [P30 DK063720, 1S10OD021822-01]
- Larry L. Hillblom Foundation
- Juvenile Diabetes Research Foundation Center of Excellence in Northern California
- Parker Institute for Cancer Immunotherapy
- Cancer Research Institute
- Burroughs Wellcome Fund
- National Institutes of Health [K08CA230188]
- Arsenal Biosciences
- NSF GRFP
- Stanford Graduate Fellowship
- Invitae
- NIH and Rheumatology Research Foundation
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This study identified a novel germline gain-of-function mutation that causes T1D in CD8+ T cells, with experiments demonstrating the impact of STAT3-GOF on autoimmune diabetes and revealing the pathogenesis of the disease, providing new insights for further research on diabetes.
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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