CD4+Foxp3+ regulatory T cells suppress [gamma][delta] T-cell effector functions in a model of T-cell-induced mucosal inflammation

CD4+CD25+Foxp3+ regulatory T (TREG) cells are critical mediators of peripheral immune tolerance, and abrogation of their function provokes a variety of autoimmune and inflammatory states including inflammatory bowel disease. In this study, we investigate the functional dynamics of TREG-cell responses in a CD4+ T-cell-induced model of intestinal inflammation in [alpha][beta] T-cell-deficient (TCR-[beta]-/-) hosts to gain insights into the mechanism and cellular targets of suppression in vivo. We show that CD4+ T effector cell transfer into T-cell-deficient mice rapidly induces mucosal inflammation and colitis development, which is associated with prominent Th1 and Th17 responses. Interestingly, we unveil a prominent role for resident [gamma][delta] T cells in mucosal inflammation as they promote Th1 and particularly Th17 responses in the early phase of inflammation, thus exacerbating colitis development. We further demonstrate that CD4+CD25+Foxp3+ TREG cells readily inhibit these responses and mediate disease protection, which correlates with their accumulation in the draining LN and lamina propria. Moreover, TREG cells can directly suppress [gamma][delta] T-cell expansion and cytokine production in vitro and in vivo, suggesting a pathogenic role of [gamma][delta] T cells in intestinal inflammation. Thus, functional alterations in TREG cells provoke dysregulated CD4+ and [gamma][delta] T-cell responses to commensal antigens in the intestine. [PUBLICATION ABSTRACT]