In vitro activated CD4+ T cells from interferon‐gamma (IFN‐γ)‐deficient mice induce intestinal inflammation in immunodeficient hosts
To investigate the role of IFN‐γ in the immunopathogenesis of inflammatory bowel disease (IBD), severe combined immunodeficient (SCID) mice were transplanted with in vitro activated CD4+ T cells from either wild‐type (WT) or IFN‐γ‐deficient (IFN‐γKO) BALB/c mice. In vitro, the two types of T cells displayed comparable proliferation rates and production of tumour necrosis factor‐alpha (TNF‐α), IL‐2, IL‐4 and IL‐10 after concanavalin A (Con A) stimulation. When transplanted into SCID mice, WT CD4+ blasts induced a lethal IBD, whereas IFN‐γKO blasts induced a less severe intestinal inflammation with moderate weight loss. Intracellular cytokine staining of lamina propria lymphocytes (LPL) revealed comparable fractions of CD4+ T cells positive for TNF‐α, IL‐2 and IL‐10 in the two groups of transplanted SCID mice, whereas a two‐to‐three‐fold increase in the fraction of IL‐4‐positive cells was found in IFN‐γKO‐transplanted SCID mice. Flow cytometric analyses showed strong up‐regulation of MHC class II expression of colonic epithelial cells of WT‐CD4+ T cell‐transplanted compared with IFN‐γKO‐transplanted SCID mice. A significantly higher fraction of CD4+ LPL were found to enter the cell cycle, i.e. to incorporate bromo‐dexoy‐uridine, and to undergo apoptosis in vivo in WT‐transplanted compared with IFN‐γKO‐transplanted SCID mice. These data point towards an important role for IFN‐γ in the development of IBD in SCID mice. The inflammation might be initiated and subsequently enhanced by the ability of IFN‐γ to induce denovo MHC class II expression in the colonic epithelium, a change which could lead to increased antigen processing and production of local proinflammatory cytokines, CD4+ T cell turnover and thereby to exaggeration of disease.