Abstract
T cells producing IFNγ play a pathogenic role in the development of inflammatory bowel disease (IBD). To investigate the functions of CD1d-dependent invariant natural killer T (iNKT) cells in experimental colitis induced in Yeti mice with dysregulated expression of IFNγ, we generated iNKT cell-deficient Yeti/CD1d KO mice and compared colitis among WT, CD1d KO, Yeti, and Yeti/CD1d KO mice following DSS treatment. We found that deficiency of iNKT cells exacerbated colitis and disease pathogenesis was mainly mediated by NK1.1+CD8+ T cells. Furthermore, the protective effects of iNKT cells correlated with up-regulation of regulatory T cells. Taken together, our results have demonstrated that CD1d-dependent iNKT cells and CD1d-independent NK1.1+CD8+ T cells reciprocally regulate the development of intestinal inflammatory responses mediated by IFNγ-dysregulation. These findings also identify NK1.1+CD8+ T cells as novel target cells for the development of therapeutics for human IBD.
Highlights
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that is caused by dysregulated immune responses to host intestinal bacterial flora [1]
Since it has been reported that IFNγ KO mice are protected from dextran sulfate sodium (DSS)-induced colitis [18], we examined whether dysregulated IFNγ expression in heterozygous Yeti mice, in which abnormal IFNγ secretion occurs due to modification of the 3′ -untranslated region (UTR) of the IFNγ gene [16], influences colitis severity
We have demonstrated here that the severity of low dose DSS (1.5%)-induced colitis is exacerbated in heterozygous Yeti mice on an natural killer T (NKT) cell-deficient background, indicating that invariant NKT (iNKT) cells are essential for maintaining intestinal homeostasis in the context of IFNγ-mediated inflammation
Summary
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that is caused by dysregulated immune responses to host intestinal bacterial flora [1]. NKT cells, defined by expression of both NK iNKT Cells Suppress DSS Colitis cell markers (NK1.1 or DX5) and T cell markers (TCRβ or CD3) and restriction by the MHC class I-related protein CD1d, display several subsets with distinct cytokine profiles in gastrointestinal lymphoid tissues, including Peyer’s patches (PP), lamina propria (LP), and mesenteric lymph nodes (MLN) of the small and large intestine [6]. A role of CD1d-restricted type I NKT cells, called invariant NKT (iNKT) cells because of the expression of an invariant TCR α chain (Vα14-Jα18 in mice and Vα24Jα18 in humans), in regulating the development of IBD is well-established. CD1d-independent NK1.1+ T cells have been identified in the intestinal tissues of CD1d knockout (KO) mice [13, 14], but their potential contribution to the pathogenesis of colitis has not been explored
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