intestine are particularly efficient for the peripheral conversion of Tregs via TGF-band retinoic acid-dependent mechanisms. Tregs that do not express FoxP3 but are functionally suppressive both in vitro and in vivo include Tr1 cells, which are defined by the production of IL-10 and can be induced by oral administration of antigen, in vitro culture with IL-10 or exposure to immature DCs. Another subset of Tregs, Th3 cells, suppresses immune responses in a TGF-b-dependent fashion. Recent data have suggested that Th3 cells may function by inducing de novo FoxP3 Tregs via TGF-b [4]. Indeed, we have reported that inhibition of TGF-b1 interferes with the induction of mucosal Tregs [5]. Disturbances in Treg number and function are associated with immune-mediated disorders. The inf lammatory bowel diseases (IBDs) include ulcerative colitis and Crohn’s disease, and are chronic diseases characterized by infiltration of inflammatory cells into the lamina propria of the intestinal tract. Data from patients and animal models suggest that IBD results from an aberrant immune response to the intestinal microflora [6]. In support of this hypothesis, genetic susceptibility to IBD in humans is associated with variations in genes that encode proteins relevant to both innate and adaptive immunity, including NOD2, ATG16L1, IL-12B, STAT3 and the IL-23 receptor (IL-23R) [7]. In addition, data from animal models demonstrate that intact intestinal flora are necessary for the development of IBD, and antibiotics and probiotics have been demonstrated to be beneficial under certain circumstances in the treatment of patients with IBD [8]. As Tregs are thought to play a critical role in limiting inflammation in response to these nonpathogenic antigens, defects in this T-cell subset The gut mucosal immune system is the largest lymphoid organ in the body. This site undergoes continuous antigenic challenges from food antigens, antigens of the abundant normal bacterial flora and pathogens. Despite this constant antigenic stimulation, controlled inf lammatory responses and suppression of inflammation appear to be the rule. Apparently, the gut immune system effectively differentiates the potentially harmful antigenic signals from the high background noise of food and bacterial antigens. This tight regulation required to maintain homeostasis is achieved through multiple nonimmune and immune factors [1]. Regulatory pathways mediated by regulatory T cells (Tregs) are essential homeostatic mechanisms. Distinct Treg subsets coexist in the intestinal mucosa and mesenteric lymph nodes. These include the ‘natural’ and ‘adaptive’ CD4 forkhead box p3 (FoxP3) Tregs, as well as Tr1 and Th3 cells. Tregs that develop in the thymus are referred to as ‘natural’ Tregs (nTregs). In addition to their natural counterparts, Tregs can develop in response to stimuli in the periphery and these have been termed ‘adaptive’ Tregs. A subset of adaptive Tregs express FoxP3, making them difficult to distinguish from their natural counterparts. In murine CD4 T cells, FoxP3 can be induced in response to activation of the T-cell receptor in the presence of TGF-b and confers suppressor function. TGF-b is also necessary for the induction of Th17 effector cells, but this requires IL-6 [2]. Interestingly, inducible Tregs (iTregs), but not nTregs, are resistant to Th17 conversion by IL-6 [3]. The intestinal environment appears to be an important site for the generation of Tregs, as dendritic cells (DCs) from the mesenteric lymph nodes and small