Justin E Johnson, Kriti Agrawal, Rafia S Al-Lamki, Fengrui Zhang, Wang D Xi, Samuel Liburd, Zsuzsanna Zsuzsanna, Leonel Rodriguez, Andrew J Martins, Esen Sefik, Richard Flavell, Marie E. Robert, Jordan S Pober
{"title":"The Multiple Roles of Gamma Interferon in Intraepithelial T Cell-Villous Enterocyte Interactions in Active Celiac Disease","authors":"Justin E Johnson, Kriti Agrawal, Rafia S Al-Lamki, Fengrui Zhang, Wang D Xi, Samuel Liburd, Zsuzsanna Zsuzsanna, Leonel Rodriguez, Andrew J Martins, Esen Sefik, Richard Flavell, Marie E. Robert, Jordan S Pober","doi":"10.1101/2024.09.03.610908","DOIUrl":null,"url":null,"abstract":"We identified molecular interactions between duodenal enterocytes and intraepithelial T cells in celiac disease (CeD) vs normal controls. We observed an expected increased ratio of T cells [bearing either T cell receptor (TCR) αβ and γδ ; and mostly activated cytotoxic T lymphocytes (CTLs) expressing granzyme B, CD45RO, Ki67 and Nur 77 proteins as well as IFNγ mRNA] to villous enterocytes. Few T cells (<5%) express NKG2C or DAP12 proteins. CeD villous enterocytes express an IFNγ signature (by single cell RNA sequencing and nuclear phopho-STAT1 and HLA-DR protein staining). CeD enterocytes express increased IFNγ -inducible chemokines CCL3, CCL4, CXCL10 and CXCL11 mRNA while CeD intraepithelial T cells express reduced levels of CCR5 and CXCR3 chemokine receptors, suggesting ligand-induced downregulation. CeD enterocyte HLA-E mRNA and protein are upregulated whereas HLA-B mRNA but not protein increases. Proximity ligation detected frequent interactions of αβ and γδ TCRs with HLA-E and HLA-B but not with HLA-DR and fewer NKG2C interactions with HLA-E. We suggest that CeD IFNγ-producing TCRαβ and γδ CTLs are recruited into villous epithelium by IFNγ-induced enterocyte production of CCR5 and CXCR3-binding chemokines and kill villous enterocytes primarily by TCR engagement with class I HLA molecules, including HLA-E, likely presenting gluten peptides. The IFN-γ signature of CeD villous enterocytes is a potential biomarker of active disease and a therapeutic target.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"7 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"bioRxiv - Immunology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.09.03.610908","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
We identified molecular interactions between duodenal enterocytes and intraepithelial T cells in celiac disease (CeD) vs normal controls. We observed an expected increased ratio of T cells [bearing either T cell receptor (TCR) αβ and γδ ; and mostly activated cytotoxic T lymphocytes (CTLs) expressing granzyme B, CD45RO, Ki67 and Nur 77 proteins as well as IFNγ mRNA] to villous enterocytes. Few T cells (<5%) express NKG2C or DAP12 proteins. CeD villous enterocytes express an IFNγ signature (by single cell RNA sequencing and nuclear phopho-STAT1 and HLA-DR protein staining). CeD enterocytes express increased IFNγ -inducible chemokines CCL3, CCL4, CXCL10 and CXCL11 mRNA while CeD intraepithelial T cells express reduced levels of CCR5 and CXCR3 chemokine receptors, suggesting ligand-induced downregulation. CeD enterocyte HLA-E mRNA and protein are upregulated whereas HLA-B mRNA but not protein increases. Proximity ligation detected frequent interactions of αβ and γδ TCRs with HLA-E and HLA-B but not with HLA-DR and fewer NKG2C interactions with HLA-E. We suggest that CeD IFNγ-producing TCRαβ and γδ CTLs are recruited into villous epithelium by IFNγ-induced enterocyte production of CCR5 and CXCR3-binding chemokines and kill villous enterocytes primarily by TCR engagement with class I HLA molecules, including HLA-E, likely presenting gluten peptides. The IFN-γ signature of CeD villous enterocytes is a potential biomarker of active disease and a therapeutic target.