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) 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.

AMULET: a novel read count-based method for effective multiplet detection from single nucleus ATAC-seq data

“…3 a, b). To further study the library depth effects on AMULET’s performance, we applied it on snATAC-seq data with different library depth: (1) publicly available mouse CD45 + cells [ 16 ] and innate lymphoid cells (ILCs) data [ 17 ] and (2) down-sampled PBMC1 and PBMC2 samples at 5% increments starting at 50%. To quantify AMULET’s performance, we simulated multiplets in each sample by randomly selecting nuclei pairs and used them to calculate recall.…”

“…The islet 1, islet 2, and pooled PBMC datasets are publicly available from the Gene Expression Omnibus (GEO) repository (GSE165212 ) [25], https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE165212. Immune cell datasets from mice analyzed during the current study are available from the Gene Expression Omnibus (GEO) repository (GSE173415 [16], GSE149622 [17]), https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE173415 and https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE149622. Documentation and source code files for the AMULET framework are freely available under a GPL V3 license on GitHub at https://github.com/UcarLab/AMULET [26].…”

“…Immune cell datasets from mice analyzed during the current study are available from the Gene Expression Omnibus (GEO) repository (GSE173415 [ 16 ], GSE149622 [ 17 ]), https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE173415 and https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE149622 .…”

Sera Protein Signatures of Endometrial Cancer Lymph Node Metastases

“…In this study, STAT3 signaling was repressed in Stages I and II, but not in Stages IIIC and IV compared to Benign groups. Gain of function STAT3 mutations have been shown to promote diabetes, while inhibition of the JAK kinase upstream of STAT3 has been shown to control lymphoproliferation in a diabetes patient with a STAT3 gain of function mutation [ 45 , 46 ]. STAT3 was reported to be upregulated in early-stage endometrial cancer, and inhibition of its signaling pathway has been shown to repress endometrial cancer stem cells and tumor growth [ 47 , 48 ].…”

STAT3 Role in T-Cell Memory Formation

“…Mutations in STAT3 are also implicated in the development of autoimmune diseases, including type 1 diabetes [ 153 ]. Recently, a mouse model heterozygous for STAT3 K392R gain-of-function mutation was generated [ 154 ]. The authors demonstrated that STAT3 K392R mutation in CD8+ T cells counteracts exhaustion, increases cytotoxicity, and can accelerate the development of T1D.…”