CD4+Foxp3+ regulatory T cells suppress γδ T-cell effector functions in a model of T-cell-induced mucosal inflammation

CD4(+)CD25(+)Foxp3(+) regulatory T (T-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-REG-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(+) T-REG cells readily inhibit these responses and mediate disease protection, which correlates with their accumulation in the draining LN and lamina propria. Moreover, T-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-REG cells provoke dysregulated CD4(+) and gamma delta T-cell responses to commensal antigens in the intestine.