In studies in murine models, active suppression by IL-10-secreting Foxp3 regulatory T cells (Tregs) has emerged as an essential mechanism in colon homeostasis. However, the role of the equivalent subset in humans remains unclear, leading to suggestions that other subsets and/or mechanisms may substitute for Foxp3 Tregs in the maintenance of colon homeostasis. We recently described a new subset of CD4CD8αα T cells reactive to the gut bacterium Faecalibacterium prausnitzii and endowed with regulatory/suppressive functions. This subset is abundant in the healthy colonic mucosa, but less common in that of patients with inflammatory bowel disease (IBD). We discuss here the physiological significance and potential role of these Tregs in preventing inflammation of the gut mucosa and the potential applications of these discoveries for IBD management. DIVERSITY OF PERIPHERALLY DERIVED Tregs (pTregs) CD4 regulatory T cells (Tregs) inhibit inflammatory responses (1). They can be subdivided into natural Tregs, which differentiate in the thymus (tTreg) and peripherally derived Tregs (pTregs), which differentiate in secondary lymphoid organs or tissues (2). These populations differ in terms of their non-redundant roles: tTregs play an essential role in maintaining tolerance toward self-structures, whereas pTregs are involved in the responses to externally delivered antigens or commensal microbes. Furthermore, the tTreg population appears to be stable, whereas that of pTregs may be more labile (3). This functional dichotomy results from differences in differentiation due to exposure to different TCR ligands (self and non-self antigens, respectively) and specific factors (cytokines, route of exposure, and antigen-presenting cells) in contrasting settings (4). The two Treg subsets can also be distinguished on the basis of the presence or absence of constitutive expression of the Foxp3 transcription factor. Constitutive Foxp3 expression and more particularly, the demethylation of a specific region of the Foxp3 locus are characteristic features of tTregs (5). Three main subsets of CD4 pTregs have been described in mice: Foxp3 + CD25 + lymphocytes (3, 6), which are particularly abundant in the colon lamina propria (LP) (7) and two Foxp3 − subsets: the type 1 regulatory T (Tr1) cells and the T helper 3 (Th3) cells. The Tr1 subset secretes IL-10 and TGF-β in the absence of IL-4 and IL-17 (8–10) and is abundant in the small intestine (7). The Th3 subset may also secrete IL-10, but it differs from Tr1 in its expression of membrane-bound TGF-β (11, 12). The Tr1 Tregs are induced in vitro by IL-10 (8–10) and in vivo by TGF-β and IL-27 (9, 13) in the context of diverse immune responses (14) and upon chronic stimulation with antigens in the presence of IL-10 (10). The suppressive action of Tr1 Tregs is essentially IL-10-dependent, but it is also at least partly governed by TGF-β (8, 9). Moreover, the suppressive function of these cells may be