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

CD4 super(+)CD25 super(+)Foxp3 super(+) regulatory T (T sub(REG)) 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 T sub(REG)-cell responses in a CD4 super(+) T-cell-induced model of intestinal inflammation in [alpha][beta] T-cell-deficient (TCR-[beta] super(-/-)) hosts to gain insights into the mechanism and cellular targets of suppression in vivo. We show that CD4 super(+) 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 super(+)CD25 super(+)Foxp 3 super(+) T sub(REG) cells readily inhibit these responses and mediate disease protection, which correlates with their accumulation in the draining LN and lamina propria. Moreover, T sub(REG) 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 T sub(REG) cells provoke dysregulated CD4 super(+) and [gamma][delta] T-cell responses to commensal antigens in the intestine.