CD4CD8αα 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 CD4CD8αα (DP8α) T lymphocytes expressed most of the regulatory markers and functions of Foxp3 Treg and secreted IL-10. Strikingly, DP8α 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 DP8α 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.
INSERM, U892, Nantes, France; Université de Nantes, Nantes, France; CNRS, UMR 6299, Nantes, France.
Guillaume
G
Sarrabayrouse
INSERM, U892, Nantes, France; Université de Nantes, Nantes, France; CNRS, UMR 6299, Nantes, France.
Céline
C
Bossard
Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Joe-Marc
JM
Chauvin
EA 4273 Biometadys, Université de Nantes, Faculté de Médecine, Nantes, France.
Anne
A
Jarry
Clinique de chirurgie digestive et endocrinienne, CHU, Nantes, France; INSERM UMR 913 Nantes France, Institut des Maladies de l'Appareil Digestif, CHU Nantes, Hôpital Hotel Dieu, Nantes, France.
Guillaume
G
Meurette
ERL INSERM U1057/UMR7203, Equipe AVENIR ″Gut Microbiota and Immunity″, Faculté de Médecine Saint-Antoine, Université Pierre et Marie Curie (UPMC), Paris, Paris, France.
Elodie
E
Quévrain
Commensal and Probiotic-Host Interactions Laboratory, UMR1319 Micalis, INRA, Jouy-en-Josas, France.
Chantal
C
Bridonneau
INSERM, U892, Nantes, France; Université d'Angers, Angers, France.
Laurence
L
Preisser
EA 3826 Thérapeutiques cliniques et expérimentales des infections, Faculté de Médecine, Université de Nantes, Nantes, France.
Karim
K
Asehnoune
INSERM, U892, Nantes, France; Université de Nantes, Nantes, France; CNRS, UMR 6299, Nantes, France.
Nathalie
N
Labarrière
INSERM, U892, Nantes, France; Université de Nantes, Nantes, France; CNRS, UMR 6299, Nantes, France.
Frédéric
F
Altare
ERL INSERM U1057/UMR7203, Equipe AVENIR ″Gut Microbiota and Immunity″, Faculté de Médecine Saint-Antoine, Université Pierre et Marie Curie (UPMC), Paris, Paris, France; Commensal and Probiotic-Host Interactions Laboratory, UMR1319 Micalis, INRA, Jouy-en-Josas, France; Service de Gastroentérologie, Hôpital Saint-Antoine, Assistance Publique - Hôpitaux de Paris (APHP), Paris, France.
Harry
H
Sokol
INSERM, U892, Nantes, France; Université de Nantes, Nantes, France; CNRS, UMR 6299, Nantes, France.
Francine
F
Jotereau
D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003013:Clostridium / Q000276:immunology*; D003093:Colitis, Ulcerative / Q000276:immunology*; D003106:Colon / Q000276:immunology / Q000382:microbiology; D003110:Colonic Neoplasms / Q000276:immunology; D003424:Crohn Disease / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000166:cytology* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015704:CD4 Antigens; D016827:CD8 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; D016753:Interleukin-10