title: Exhaustion of bacteria-specific CD4 T cells and microbial translocation in common variable immunodeficiency disorders.
abstract: In the present study, we have investigated the functional profile of CD4 T cells from patients with common variable immunodeficiency (CVID), including production of cytokines and proliferation in response to bacteria and virus-derived antigens. We show that the functional impairment of CD4 T cells, including the reduced capacity to proliferate and to produce IFN-γ and IL-2, was restricted to bacteria-specific and not virus-specific CD4 T cells. High levels of endotoxins were found in the plasma of patients with CVID, suggesting that CD4 T cell dysfunction might be caused by bacterial translocation. Of note, endotoxemia was associated with significantly higher expression of programmed death 1 (PD-1) on CD4 T cells. The blockade of the PD-1-PD-L1/2 axis in vitro restored CD4 T cell proliferation capacity, thus indicating that PD-1 signaling negatively regulates CD4 T cell functions. Finally, we showed that intravenous immunoglobulin G (IVIG) treatment significantly reduced endotoxemia and the percentage of PD-1(+) CD4 T cells, and restored bacteria-specific CD4 T cell cytokine production and proliferation. In conclusion, the present study demonstrates that the CD4 T cell exhaustion and functional impairment observed in CVID patients is associated with bacterial translocation and that IVIG treatment resolves bacterial translocation and restores CD4 T cell functions.
authors.affiliation: Service of Immunology and Allergy and Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland matthieu.perreau@chuv.ch giuseppe.pantaleo@chuv.ch.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Perreau
authors.affiliation: Service of Immunology and Allergy and Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Selena
authors.initials: S
authors.lastname: Vigano
authors.affiliation: Service of Immunology and Allergy and Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Bellanger
authors.affiliation: Service of Immunology and Allergy and Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Pellaton
authors.affiliation: Service of Immunology and Allergy and Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Buss
authors.affiliation: Service of Immunology and Allergy and Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Comte
authors.affiliation: Service of Immunology and Allergy and Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Thierry
authors.initials: T
authors.lastname: Roger
authors.affiliation: INSERM U955, Université Paris Est Créteil, Groupe Henri-Mondor Albert-Chenevier, Immunologie Clinique, Vaccine Research Institute, 94010 Creteil, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lacabaratz
authors.affiliation: Service of Immunology and Allergy and Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Bart
authors.affiliation: INSERM U955, Université Paris Est Créteil, Groupe Henri-Mondor Albert-Chenevier, Immunologie Clinique, Vaccine Research Institute, 94010 Creteil, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Levy
authors.affiliation: Service of Immunology and Allergy and Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland Swiss Vaccine Research Institute, 1011 Lausanne, Switzerland matthieu.perreau@chuv.ch giuseppe.pantaleo@chuv.ch.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pantaleo
mesh_terms: D061605:Administration, Intravenous; D000704:Analysis of Variance; D000942:Antigens, Bacterial / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology; D017074:Common Variable Immunodeficiency / Q000276:immunology* / Q000382:microbiology; D016207:Cytokines / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008033:Limulus Test; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D000956:Antigens, Viral; D016207:Cytokines; D007074:Immunoglobulin G; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor