T cell receptors for antigen on intraepithelial cytolytic T lymphocytes in celiac disease engage enterocyte HLA-E and HLA-B

• 成果类型: Article
• 署名作者: Johnson, Justin E.; Agrawal, Kriti; Al-Lamki, Rafia S.; Zhang, Fengrui; Wang, Xi D.; Tobiasova, Zuzana; Taleb, Shakila A.; Liburd Jr, Samuel; Rodriguez, Leonel; Martins, Andrew J.; Flavell, Richard A.; Robert, Marie E.; Sefik, Esen; Pober, Jordan S.
• 署名单位: Yale University; Yale University; University of Cambridge; Yale University; Yale University; Yale University; Howard Hughes Medical Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2525433123
• 发表日期: 2026-02-10
• 页码: e2525433123
• 关键词: celiac disease; immunology; HLA-E; ifn-gamma; cytotoxic T cells; INTESTINAL-MUCOSA; diagnosis; association; GUIDELINES; management; responses; reveals; genes; gamma

摘要

We compared duodenal biopsies showing active celiac disease (CeD) to normal controls using single-cell RNA sequencing, cyclic immunofluorescence, RNAScope, and proximity ligation assays. There is increased infiltration of villous but not crypt epithelium T cells bearing either alpha f3 or gamma delta T cell receptors (TCRs) in CeD. Both T cell subsets are activated cytotoxic T lymphocytes (CTLs) and are the predominant mucosal source of IFN gamma. In response to this IFN gamma, villous but not crypt enterocytes show an IFN gamma signature, including nuclear phospho-STAT1 protein, class II HLA molecules and IFN gamma-inducible chemokines known to recruit CTLs (e.g., CCL3, CCL4, CXCL10, and CXCL11) and receptors for these chemokines are expressed on the infiltrating CTLs. Villous enterocytes also display increased HLA-E and HLA-B mRNAs and proteins. Bioinformatic analyses (NICHES) and proximity ligation assays show frequent binding of both alpha f3 and gamma delta TCRs with enterocyte HLA-E or HLA-B, but not HLA-DR. In contrast, NKG2C, proposed as an alternative trigger of CTL activation, is infrequentlyexpressed and shows few interactions with HLA-E. Our data suggest that activated intraepithelial CTLs produce IFN gamma which recruits additional CTLs and increases antigen-dependent killing of villous epithelium using either conventional or HLA-E antigen presentation.