| First Author | Chang JS | Year | 2012 |
| Journal | J Immunol | Volume | 189 |
| Issue | 3 | Pages | 1510-20 |
| PubMed ID | 22753943 | Mgi Jnum | J:189769 |
| Mgi Id | MGI:5446975 | Doi | 10.4049/jimmunol.1200166 |
| Citation | Chang JS, et al. (2012) Endoplasmic reticulum stress response promotes cytotoxic phenotype of CD8alphabeta+ intraepithelial lymphocytes in a mouse model for Crohn's disease-like ileitis. J Immunol 189(3):1510-20 |
| abstractText | Endoplasmic reticulum (ER) unfolded protein responses (UPR) are implicated in the pathogenesis of inflammatory bowel disease. Cytotoxic CD8alphabeta(+) intraepithelial lymphocytes (IEL) contribute to the development of Crohn's disease-like ileitis in TNF(DeltaARE/+) 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(DeltaARE/+) mice exhibited increased expression of Grp78, ATF6, ATF4, and spliced XBP1 in CD8alphabeta(+) IEL but not in CD8alphaalpha(+) IEL or in lamina propria lymphocytes. Chromatin immunoprecipitation analysis in CD8alphabeta(+) 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 CD8alphabeta(+) 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 CD8alphabeta(+) T cells showed a defect in IL-2-mediated proliferation in Grp78(-/+) mice. Adoptively transferred Grp78(-/+) CD8alphabeta(+) T cells had a decreased frequency of accumulation in the intestine of RAG2(-/-) recipient mice. The tissue pathology in TNF(DeltaARE/+) x Grp78(-/+) mice was similar to TNF(DeltaARE/+) mice, even though the cytotoxic effector functions of CD8alphabeta(+) T cells were significantly reduced. In conclusion, ER stress-associated UPR mechanisms promote the development and maintenance of the pathogenic cytotoxic CD8alphabeta(+) IEL phenotype in the mouse model of Crohn's disease-like ileitis. |
