{"doi":"10.1084/jem.20210759","title":"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.","journal":"The Journal of Experimental Medicine","year":2021,"id":161817,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":56,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":262617,"name":"Julia A. Belk","orcid":"0000-0003-4724-6158","position":1,"is_corresponding":false},{"id":295449,"name":"Alice Chan","orcid":"0000-0003-1466-7044","position":2,"is_corresponding":false},{"id":677160,"name":"Jiaxi Wang","orcid":"0000-0001-6043-9953","position":3,"is_corresponding":false},{"id":677161,"name":"Alexander R. Gupta","orcid":"0000-0002-2813-6175","position":4,"is_corresponding":false},{"id":291362,"name":"Quanming Shi","orcid":"0000-0003-2109-5048","position":5,"is_corresponding":false},{"id":285542,"name":"Nikolaos Skartsis","orcid":"0000-0001-9874-4574","position":6,"is_corresponding":false},{"id":677162,"name":"Yani Peng","orcid":"0000-0002-3711-7160","position":7,"is_corresponding":false},{"id":282725,"name":"Jonah D. Phipps","orcid":"0000-0001-9685-741X","position":8,"is_corresponding":false},{"id":235401,"name":"Dante Acenas","orcid":"0000-0003-4137-0297","position":9,"is_corresponding":false},{"id":235279,"name":"Jennifer Smith","orcid":"0000-0002-5662-1776","position":10,"is_corresponding":false},{"id":261007,"name":"Stanley Tamaki","orcid":null,"position":11,"is_corresponding":false},{"id":285543,"name":"Qizhi Tang","orcid":"0000-0001-7313-3574","position":12,"is_corresponding":false},{"id":73995,"name":"James M. Gardner","orcid":"0000-0003-3470-9520","position":13,"is_corresponding":false},{"id":21653,"name":"Ansuman T. Satpathy","orcid":"0000-0002-5167-537X","position":14,"is_corresponding":false},{"id":235418,"name":"Mark S. Anderson","orcid":"0000-0002-3093-4758","position":15,"is_corresponding":false},{"id":580704,"name":"Jeremy Warshauer","orcid":"0000-0002-5182-0637","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-18T23:44:56.409311Z","pmid":"34115115","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}