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 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.

Abbreviations used in this paper:  CRγ, common cytokine receptor γ chain , ELISA, enzyme-linked immunosorbent assay , FACS, fluorescence-activated cell sorter , FITC, fluorescein isothiocyanate , GAPDH, glyceraldehyde-3-phosphate dehydrogenase , IFN, interferon , IL, interleukin , IL-6R, interleukin-6 receptor , LCR, LightCycler Red 640 , LP, lamina propria , mAb, monoclonal antibody , PCR, polymerase chain reaction , PE, phycoerythrin , SP, spleen , TCR, T-cell receptor , TGF, transforming growth factor , TNF, tumor necrosis factor