Colitis in mice lacking the common cytokine receptor γ chain is mediated by IL-6-producing CD4+ T cells

Background & Aims: Mice that have a truncated mutation of the common cytokine receptor gamma chain (CR gamma(-/Y)) are known to spontaneously develop colitis. To identify the pathologic elements responsible for triggering this localized inflammatory disease, we elucidated and characterized aberrant T cells and their enteropathogenic cytokines in CR gamma(-/Y) mice with colitis. Methods: The histologic appearance, cell population, T-cell receptor V beta usage, and cytokine production of lamina propria lymphocytes were assessed. CR gamma(-/Y) mice were treated with anti-interleukin (IL)-6 receptor monoclonal antibody to evaluate its ability to control colitis, and splenic CD4(+) T cells from the same mouse model were adoptively transferred into SCID mice to see if they spurred the appearance of colitis. Results: We found marked thickening of the large intestine, an increase in crypt depth, and infiltration of the colonic lamina propria and submucosa with mononuclear cells in the euthymic CR gamma(-/Y) mice, but not in the athymic CR gamma(-/Y) mice, starting at the age of 8 weeks. Colonic CD4(+) T cells with high expressions of antiapoptotic Bcl-x and Bcl-2 were found to use selected subsets (V beta 14) of T-cell receptor and to exclusively produce IL-6. Treatment of CR gamma(-/Y) mice with anti-IL-6 receptor monoclonal antibody prevented the formation of colitis via the induction of apoptosis in IL-6-producing CD4(+) T cells. Adoptive transfer of pathologic CD4(+) T cells induced colitis in the recipient SCID mice. Conclusions: Colonic IL-6-producing thymus-derived CD4(+) T cells are responsible for the development of colitis in CR gamma(-/Y) mice.