CD 4 CD 8 aa Lymphocytes , A Novel Human Regulatory T Cell Subset Induced by Colonic Bacteria and Deficient in Patients with Inflammatory Bowel Disease

How the microbiota affects health and disease is a crucial question. In mice, gut Clostridium bacteria are potent inducers of colonic interleukin (IL)-10-producing Foxp3 regulatory T cells (Treg), which play key roles in the prevention of colitis and in systemic immunity. In humans, although gut microbiota dysbiosis is associated with immune disorders, the underlying mechanism remains unknown. In contrast with mice, the contribution of Foxp3 Treg in colitis prevention has been questioned, suggesting that other compensatory regulatory cells or mechanisms may exist. Here we addressed the regulatory role of the CD4CD8 T cells whose presence had been reported in the intestinal mucosa and blood. Using colonic lamina propria lymphocytes (LPL) and peripheral blood lymphocytes (PBL) from healthy individuals, and those with colon cancer and irritable bowel disease (IBD), we demonstrated that CD4CD8aa (DP8a) T lymphocytes expressed most of the regulatory markers and functions of Foxp3 Treg and secreted IL-10. Strikingly, DP8a LPL and PBL exhibited a highly skewed repertoire toward the recognition of Faecalibacterium prausnitzii, a major Clostridium species of the human gut microbiota, which is decreased in patients with IBD. Furthermore, the frequencies of DP8a PBL and colonic LPL were lower in patients with IBD than in healthy donors and in the healthy mucosa of patients with colon cancer, respectively. Moreover, PBL and LPL from most patients with active IBD failed to respond to F. prausnitzii in contrast to PBL and LPL from patients in remission and/or healthy donors. These data (i) uncover a Clostridium-specific IL-10-secreting Treg subset present in the human colonic LP and blood, (ii) identify F. prausnitzii 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. Citation: Sarrabayrouse G, Bossard C, Chauvin J-M, Jarry A, Meurette G, et al. (2014) CD4CD8aa Lymphocytes, A Novel Human Regulatory T Cell Subset Induced by Colonic Bacteria and Deficient in Patients with Inflammatory Bowel Disease. PLoS Biol 12(4): e1001833. doi:10.1371/journal.pbio. 1001833 Academic Editor: Philippa Marrack, National Jewish Medical and Research Center/Howard Hughes Medical Institute, United States of America Received June 20, 2013; Accepted February 26, 2014; Published April 8, 2014 Copyright: 2014 Sarrabayrouse et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The work was supported by grants from FP7, ANR and Cancéropôle Grand Ouest 2009. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Abbreviations: APC, antigen presenting cell; B, Bacteroides thetaiotaomicron; CC, colon cancer; DC, dendritic cell; DP, double positive; DP8a, double positive CD4CD8aa; E, Escherichia coli; F, Faecalibacterium prausnitzii; IBD, Inflammatory Bowel Disease; IEL, intraepithelial lymphocyte; IFN-c, interferon gamma; IL, interleukin; L, Lactobacillus casei; LP, lamina propria; LPL, lamina propria lymphocytes; PBL, peripheral blood lymphocytes; PBMC, peripheral blood mononuclear cell; TCR, T cell receptor; TGF, transforming growth factor; TNF-a, tumor necrosis factor-alpha; Treg, regulatory T cells; UC, ulcerative colitis. * E-mail: frederic.altare@inserm.fr (FA); jotereau@nantes.inserm.fr (FJ)