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

Abstract

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. 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. 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. Colonic IL-6-producing thymus-derived CD4 + T cells are responsible for the development of colitis in CR gamma -/Y mice.