Evidence that CD4+, but not CD8+ T cells are responsible for murine interleukin‐2‐deficient colitis

Abstract

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 TcRαβ, rather than to the TcRγδ IEL subset. IL‐2^null animals crossed with major histocompatibility complex class I‐deficient mice [IL‐2^null × β₂ microglobulin (β₂m^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 × β₂m^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 × β₂m^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 × β₂m^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.