Endoplasmic reticulum stress response promotes cytotoxic phenotype of CD8αβ ⁺ intraepithelial lymphocytes in a mouse model for Crohn's disease-like ileitis

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 TNF ^ΔARE/+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 TNF ^ΔARE/+ 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 TNF ^ΔARE/+ x Grp78 ^-/+ mice was similar to TNF ^ΔARE/+ 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.