EVIDENCE THAT CD4(+), BUT NOT CD8(+) T-CELLS ARE RESPONSIBLE FOR MURINE INTERLEUKIN-2-DEFICIENT COLITIS

Mice deficient in interleukin-2 production (IL-2(null) mice) develop colonic inflammation closely resembling ulcerative colitis in humans. Although this disease is marked by substantial infiltration of the colon by CD8(+) and CD4(+) T lymphocytes, no function has yet been assigned to these T cell subsets in the development of colitis in the IL-2(null) mouse. For the present study, we investigated the involvement of T lymphocytes in the onset of colitis in IL-2(null) mice, and examined the possible role played by cytotoxic T cells. Both lamina propria lymphocytes (LPL) and intraepithelial lymphocytes (IEL) of the colon of IL-2(null) mice were potently cytotoxic ex vivo in short-term redirected cytotoxic lymphocyte (CTL) assays. In contrast, colonic T cells of wild-type animals showed little or no constitutive cytotoxic T cell activity. Colonic CTL were detectable prior to the appearance of disease in IL-2(null) animals and CTL activity was confined to the TcR alpha beta, rather than to the TcR gamma delta TEL subset. IL-2(null) animals crossed with major histocompatibility complex class I-deficient mice [IL-2(null) x beta(2) microglobulin (beta(2)m(null)) mice] also developed colitis, which appeared even earlier than in most IL-2(null) mice. These findings suggest that neither CD8(+) IEL nor LPL were causal in the onset of colitis in IL-2(null) animals. In IL-2(null) x beta(2)m(null) mice, an ulcerative colitis-like disease was evident from histological studies and immunohistological staining which showed very large numbers of CD4(+) lymphocytes within the intestinal mucosa. Significant ex vivo killing by CD4(+) T cells was observed in IL-2(null) x beta(2)m(null) animals, although this required an extended incubation time compared to colonic CD8(+) T cells. Peripheral as well as colonic CD4(+) T cells in IL-2(null) and IL-2(null) x beta(2)m(null) animals, were activated as judged by their cell surface phenotype (CD45RB(lo), L-selectin(lo) and CD69(+)). In light of these findings, we propose that infiltrating CD4(+), but not CD8(+) T cells are central to the inflammation observed in the intestinal mucosa in IL-2(null) colitis.