How the microbiota affects health and disease is a crucial question. malignancy and irritable bowel disease (IBD), we exhibited that CD4CD8 (DP8) T lymphocytes expressed most of the regulatory markers and functions of Foxp3 Treg and secreted IL-10. Strikingly, DP8 LPL and PBL exhibited a highly skewed repertoire toward the recognition of species of the human gut microbiota, which is usually decreased in patients with IBD. Furthermore, the frequencies of DP8 PBL and colonic LPL were lower in patients with IBD than in healthy donors and in the healthy mucosa of patients with colon malignancy, respectively. Moreover, PBL and LPL from most patients with active IBD 169939-94-0 failed to respond to in contrast to PBL and LPL from patients in remission and/or healthy donors. These data (i) uncover a as a major inducer of these Treg, (iii) argue that these cells contribute to the control or prevention of colitis, opening new diagnostic and therapeutic strategies for IBD, and (iv) provide new tools to address the systemic impact of both these Treg and the intestinal microbiota on the human immune homeostasis. Author Summary It has become evident that bacteria in our gut affect health and disease, but less is usually known about how they do this. Recent studies in mice showed that gut Clostridium bacteria and their metabolites can activate regulatory T cells (Treg) that in turn mediate tolerance to signals that would ordinarily cause inflammation. In this study we identify a subset of human T lymphocytes, designated CD4CD8 T cells that are present in the surface lining of the colon and in the blood. We demonstrate Treg activity and show these cells to be activated by microbiota; we identify in individuals suffering from inflammatory bowel disease (IBD), and accordingly the CD4CD8 T cells are decreased in the KDELC1 antibody blood and gut of patients with IBD. We argue that CD4CD8 colonic Treg probably help control or prevent IBD. These data open the road to new diagnostic and therapeutic strategies for the management of IBD and provide new tools to address the impact of the intestinal microbiota on the human immune system. Introduction The gastrointestinal tract hosts a huge number of bacteria species. In mice, these bacteria play a major role in shaping local and systemic immune responses, notably by the induction of different effector and regulatory T cell subsets, whose adequate balance is usually required for the maintenance of gut homeostasis . It may be postulated that this balance relies on the microbiota composition, as suggested by the observation that dysbiosis are frequent in chronic immune disorders, especially Inflammatory Bowel Disease (IBD) C. Nonetheless, data on how the microbiota composition may 169939-94-0 impact the disease process are still lacking and in particular the presence and potential 169939-94-0 role of microbiota-induced regulatory T cells (Treg) in humans remain to be resolved . CD4 T cells 169939-94-0 that express the transcription factor fork head box p3 (Foxp3) are the best-known Treg. Some differentiate in the thymus in response to self-antigens and prevent self-reactive immune responses ,. Others differentiate in the periphery under various conditions including chronic challenges by non-self antigens, such as commensal bacteria, and are strong contributors to tissue homeostasis . In mice, a recent study highlighted that bacteria are outstanding inducers of Foxp3 Treg in the colonic mucosa . Additionally, some of these Treg conveying microbiota-specific T cell receptor (TCR) suggested that their induction involved the cognate recognition of bacterial antigens . Foxp3 Treg are also present in the human gut mucosa, but their exact origin, distribution, and contribution to IBD prevention remain to be elucidated. Given that individuals with FOXP3 mutations do not usually develop colitis and that intestinal inflammation is usually not associated with a decrease in the number of Foxp3 Treg, it has been.