OX40L/OX40 axis impairs follicular and natural Treg function in human SLE

Autor: Cécile Contin-Bordes, Edouard Forcade, Patrick Blanco, Jean-François Viallard, Jean-Luc Pellegrin, Noémie Gensous, Virginia Pascual, Estibaliz Lazaro, Emeline Levionnois, Pierre Duffau, Julien Seneschal, Lionel Couzi, Isabelle Douchet, Christophe Richez, Marc Scherlinger, Thierry Schaeverbeke, C. Jacquemin, Marie-Elise Truchetet, Jean-François Augusto
Přispěvatelé: Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Bordeaux (UB), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service de médecine interne et maladies infectieuses [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Saint-André, Immunology and Allergy, University Hospital and School of Medicine, Service de Néphrologie-transplantation-dialyse [Bordeaux], Service de médecine interne (CH F. Quesnay), Centre hospitalier F. Quesnay, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie, Baylor Institute for Immunology Research (BIIR), Immunology from Concept and Experiments to Translation (ImmunoConcept), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
Myeloid
T-Lymphocytes
[SDV]Life Sciences [q-bio]
T cell
Antigen-Presenting Cells
Down-Regulation
OX40 Ligand
chemical and pharmacologic phenomena
Lymphocyte Activation
medicine.disease_cause
T-Lymphocytes
Regulatory
Immunoglobulin secretion
Autoimmune Diseases
Autoimmunity
03 medical and health sciences
immune system diseases
medicine
Humans
Lupus Erythematosus
Systemic
Myeloid Cells
skin and connective tissue diseases
Antigen-presenting cell
Cell Proliferation
Immunity
Cellular
Lupus erythematosus
Systemic lupus erythematosus
business.industry
FOXP3
Forkhead Transcription Factors
hemic and immune systems
Dendritic Cells
T-Lymphocytes
Helper-Inducer
General Medicine
Receptors
OX40
medicine.disease
030104 developmental biology
medicine.anatomical_structure
Immunology
Cytokines
Female
business
Research Article
Zdroj: JCI Insight
JCI Insight, American Society for Clinical Investigation, 2018, 3 (24), pp.e122167. ⟨10.1172/jci.insight.122167⟩
ISSN: 2379-3708
Popis: International audience; Tregs are impaired in human systemic lupus erythematosus (SLE) and contribute to effector T cell activation. However, the mechanisms responsible for the Treg deficiency in SLE remain unclear. We hypothesized that the OX40L/OX40 axis is implicated in Treg and regulatory follicular helper T (Tfr) cell dysfunction in human SLE. OX40L/OX40 axis engagement on Tregs and Tfr cells not only specifically impaired their ability to regulate effector T cell proliferation, but also their ability to suppress T follicular helper (Tfh) cell-dependent B cell activation and immunoglobulin secretion. Antigen-presenting cells from patients with active SLE mediated Treg dysfunction in an OX40L-dependent manner, and OX40L-expressing cells colocalized with Foxp3+ cells in active SLE skin lesions. Engagement of the OX40L/OX40 axis resulted in Foxp3 downregulation in Tregs, and expression in SLE Tregs correlated with the proportion of circulating OX40L-expressing myeloid DCs. These data support that OX40L/OX40 signals are implicated in Treg dysfunction in human SLE. Thus, blocking the OX40L/OX40 axis appears to be a promising therapeutic strategy.
Databáze: OpenAIRE
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