Conserved γδ T cell selection by BTNL proteins limits progression of human inflammatory bowel disease

• 成果类型: Article
• 署名作者: Dart, Robin J.; Zlatareva, Iva; Vantourout, Pierre; Theodoridis, Efstathios; Amar, Ariella; Kannambath, Shichina; East, Philip; Recaldin, Timothy; Mansfield, John C.; Lamb, Christopher A.; Parkes, Miles; Irving, Peter M.; Prescott, Natalie J.; Hayday, Adrian C.
• 署名单位: University of London; King's College London; Francis Crick Institute; Guy's & St Thomas' NHS Foundation Trust; University of London; King's College London; University of London; King's College London; Francis Crick Institute; Newcastle University - UK; Newcastle Upon Tyne Hospitals NHS Foundation Trust; Newcastle University - UK; University of Cambridge; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8595
• DOI: 10.1126/science.adh0301
• 发表日期: 2023-09-15
• 页码: 1169-+
• 关键词: maintenance therapy; monoclonal-antibody; intestinal inflammation; enrichment analysis; crohns-disease; expression; population; receptor; lymphocytes; susceptibility

摘要

Murine intraepithelial gamma delta T cells include distinct tissue-protective cells selected by epithelial butyrophilin-like (BTNL) heteromers. To determine whether this biology is conserved in humans, we characterized the colonic gamma delta T cell compartment, identifying a diverse repertoire that includes a phenotypically distinct subset coexpressing T cell receptor V gamma 4 and the epithelium-binding integrin CD103. This subset was disproportionately diminished and dysregulated in inflammatory bowel disease, whereas on-treatment CD103(+)gamma delta T cell restoration was associated with sustained inflammatory bowel disease remission. Moreover, CD103(+)V gamma 4(+) cell dysregulation and loss were also displayed by humans with germline BTNL3/BTNL8 hypomorphism, which we identified as a risk factor for penetrating Crohn's disease (CD). Thus, BTNL-dependent selection and/or maintenance of distinct tissue-intrinsic gamma delta T cells appears to be an evolutionarily conserved axis limiting the progression of a complex, multifactorial, tissue-damaging disease of increasing global incidence.