The Multiple Roles of Gamma Interferon in Intraepithelial T Cell-Villous Enterocyte Interactions in Active Celiac Disease

Abstract

AbstractWe 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 or 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 TCR αβ 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.