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

• Published in: JCI insight Vol. 3; no. 24
• Main Authors: Jacquemin, Clément, Augusto, Jean-François, Scherlinger, Marc, Gensous, Noémie, Forcade, Edouard, Douchet, Isabelle, Levionnois, Emeline, Richez, Christophe, Lazaro, Estibaliz, Duffau, Pierre, Truchetet, Marie-Elise, Seneschal, Julien, Couzi, Lionel, Pellegrin, Jean-Luc, Viallard, Jean-François, Schaeverbeke, Thierry, Pascual, Virginia, Contin-Bordes, Cécile, Blanco, Patrick
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 20.12.2018
• Subjects: Antigen-Presenting Cells; Autoimmune Diseases - immunology; Cell Proliferation; Cytokines; Dendritic Cells - immunology; Down-Regulation; Female; Forkhead Transcription Factors - metabolism; Humans; Immunity, Cellular - immunology; Life Sciences; Lupus Erythematosus, Systemic - immunology; Lymphocyte Activation; Male; Myeloid Cells - immunology; OX40 Ligand - immunology; OX40 Ligand - metabolism; Receptors, OX40 - immunology; Receptors, OX40 - metabolism; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Autoimmunity; Lupus; Immunology; Autoimmune diseases; Cellular immune response
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.122167

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.