In vitro activated CD4(+) T cells from interferon-gamma (IFN-gamma)-deficient mice induce intestinal inflammation in immunodeficient hosts

To investigate the role of IFN-gamma in the immunopathogenesis of inflammat ory bowel disease (IBD), severe combined immunodeficient (SCID) mice were t ransplanted with in vitro activated CD4(+) T cells from either wild-type (W T) or IFN-gamma-deficient (IFN-gamma KO) BALB/c mice. In vitro, the two typ es of T cells displayed comparable proliferation rates and production of tu mour necrosis factor-alpha (TNF-alpha), IL-2, IL-4 and IL-10 after concanav alin A (Con A) stimulation. When transplanted into SCID mice, WT CD4(+) bla sts induced a lethal IBD, whereas IFN-gamma KO 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-alpha, IL-2 and IL-10 in the two groups of transplanted SCID mice, whereas a two-to-three-fold increase in the frac tion of IL-4-positive cells was found in IFN-gamma KO-transplanted SCID mic e. Flow cytometric analyses showed strong up-regulation of MHC class II exp ression of colonic epithelial cells of WT-CD4(+) T cell-transplanted compar ed with IFN-gamma KO-transplanted SCID mice. A significantly higher fractio n of CD4(+) LPL were found to enter the cell cycle, i.e. to incorporate bro mo-dexoy-uridine, and to undergo apoptosis in vivo in WT-transplanted compa red with IFN-gamma KO-transplanted SCID mice. These data point towards an i mportant role for IFN-gamma in the development of IBD in SCID mice. The inf lammation might be initiated and subsequently enhanced by the ability of IF N-gamma to induce de novo 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 e xaggeration of disease.