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

Abstract

Background & Aims: Mice that have a truncated mutation of the common cytokine receptor γ chain (CRγ-/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 CRγ-/Y mice with colitis. Methods: The histologic appearance, cell population, T-cell receptor Vβ usage, and cytokine production of lamina propria lymphocytes were assessed. CRγ-/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 CRγ-/Y mice, but not in the athymic CRγ-/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 (Vβ14) of T-cell receptor and to exclusively produce IL-6. Treatment of CRγ-/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 CRγ-/Y mice. © 2005 by the American Gastroenterological Association.