Endoplasmic Reticulum Stress Response Promotes Cytotoxic Phenotype of CD8αβ+ Intraepithelial Lymphocytes in a Mouse Model for Crohn’s Disease-like Ileitis

Abstract

Endoplasmic reticulum (ER) unfolded protein responses (UPR) are implicated in the pathogenesis of inflammatory bowel disease. Cytotoxic CD8αβ+ intraepithelial lymphocytes (IEL) contribute to the development of Crohn’s disease-like ileitis in TNFΔARE/+ mice. In this study, we characterized the role of ER-UPR mechanisms in contributing to the disease-associated phenotype of cytotoxic IEL under conditions of chronic inflammation. Inflamed TNFΔARE/+ mice exhibited increased expression of Grp78, ATF6, ATF4, and spliced XBP1 in CD8αβ+ IEL but not in CD8αα+ IEL or in lamina propria lymphocytes. Chromatin immunoprecipitation analysis in CD8αβ+ T cells showed selective recruitment of ER-UPR transducers to the granzyme B gene promoter. Heterozygous Grp78−/+ mice exhibited an attenuated granzyme B-dependent cytotoxicity of CD8αβ+ T cells against intestinal epithelial cells, suggesting a critical activity of this ER-associated chaperone in maintaining a cytotoxic T cell phenotype. Granzyme B-deficient CD8αβ+ T cells showed a defect in IL-2–mediated proliferation in Grp78−/+ mice. Adoptively transferred Grp78−/+ CD8αβ+ T cells had a decreased frequency of accumulation in the intestine of RAG2−/− recipient mice. The tissue pathology in TNFΔARE/+ × Grp78−/+ mice was similar to TNFΔARE/+ mice, even though the cytotoxic effector functions of CD8αβ+ T cells were significantly reduced. In conclusion, ER stress-associated UPR mechanisms promote the development and maintenance of the pathogenic cytotoxic CD8αβ+ IEL phenotype in the mouse model of Crohn’s disease-like ileitis.