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 αβ T-cell-deficient (TCR-β^−/−) 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 γδ 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 γδ T-cell expansion and cytokine production in vitro and in vivo, suggesting a pathogenic role of γδ T cells in intestinal inflammation. Thus, functional alterations in T_REG cells provoke dysregulated CD4⁺ and γδ T-cell responses to commensal antigens in the intestine. [ABSTRACT FROM AUTHOR]