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 (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 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+ 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 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 TREG cells provoke dysregulated CD4+ and γδ T‐cell responses to commensal antigens in the intestine.