CD8+ cytotoxic T cells induce relapsing colitis in normal mice

Background & Aims: Most mouse models of IBD have emphasized an effector role of type-1 CD4(+) T cells in colitis. The aim of this study was to develop a model of antigen-specific relapsing colitis to investigate the relative contribution of CD4(+) and CD8(+) effectors. Methods: Balb/C mice were sensitized and challenged with a suboptimal dose of 2.4 dinitrobenzene sulfonic acid to generate a colonic delayed-type hypersensitivity response. The respective role of CD4(+) and CD8(+) T cells in the initiation of colitis was analyzed by in vivo monoclonal antibody depletion and cell-transfer experiments. Dynamic and function of the colitogenic effectors were studied by immunohistochemistry, fluorescence-activated cell sorter analysis, enzyme-linked immunospot assay, quantitative polymerase chain reaction, and in vivo CTL assays. Results: Relapsing colitis rapidly occurred only after challenge of previously sensitized mice. Interferon-gamma-producing cytotoxic CD8(+) T cells (Tc1) specific for hapten-modified self-proteins were generated in colon-draining lymph nodes on day 5 after sensitization, before the onset of disease. These CD8(+) T cells were rapidly recruited upon challenge into colon lamina propria as granzyme B-expressing effectors exerting ex vivo cytotoxicity against syngeneic hapten-modified colonic epithelial cells. Colitis was prevented by in vivo antibody depletion of CD8(+), but not of CD4(+), T cells and could be induced in naive recipients within 48 hours after transfer of CD8(+), but not CD4(+), T cells purified from sensitized mice. Conclusions: Our data show that antigen-specific CD8(+) T cells can induce relapsing colitis in normal mice an suggest that the cytolytic function of CD8 Tc1 against epithelial cells may initiate the intestinal inflammatory process.