OX40L/OX40 axis impairs follicular and natural Treg function in human SLE.
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.
['Jacquemin|Clément|C|', 'Augusto|Jean-François|JF|', 'Scherlinger|Marc|M|', 'Gensous|Noémie|N|', 'Forcade|Edouard|E|', 'Douchet|Isabelle|I|', 'Levionnois|Emeline|E|', 'Richez|Christophe|C|', 'Lazaro|Estibaliz|E|', 'Duffau|Pierre|P|', 'Truchetet|Marie-Elise|ME|', 'Seneschal|Julien|J|', 'Couzi|Lionel|L|', 'Pellegrin|Jean-Luc|JL|', 'Viallard|Jean-François|JF|', 'Schaeverbeke|Thierry|T|', 'Pascual|Virginia|V|', 'Contin-Bordes|Cécile|C|', 'Blanco|Patrick|P|']
D000938:Antigen-Presenting Cells D001327:Autoimmune Diseases D049109:Cell Proliferation D016207:Cytokines D003713:Dendritic Cells D015536:Down-Regulation D005260:Female D051858:Forkhead Transcription Factors D006801:Humans D007111:Immunity, Cellular D008180:Lupus Erythematosus, Systemic D008213:Lymphocyte Activation D008297:Male D022423:Myeloid Cells D053278:OX40 Ligand D053262:Receptors, OX40 D013601:T-Lymphocytes D006377:T-Lymphocytes, Helper-Inducer D050378:T-Lymphocytes, Regulatory
Lupus Autoimmune diseases Autoimmunity Cellular immune response Immunology