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

Jung Su Chang, Soeren Ocvirk, Emanuel Berger, Sigrid Kisling, Uli Binder, Arne Skerra, Amy S. Lee, Dirk Haller

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19 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)1510-1520
Number of pages11
JournalJournal of Immunology
Volume189
Issue number3
DOIs
Publication statusPublished - Aug 1 2012

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ASJC Scopus subject areas

  • Immunology

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