Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis
Marc Scherlinger, Vivien Guillotin, Isabelle Douchet, Pierre Vacher, Andréa Boizard-Moracchini, Jean‐Philippe Guégan, Anne Garreau, Nathalie Merillon, Agathe Vermorel, Emmanuel Ribeiro, Irène Machelart, Estibaliz Lazaro, Lionel Couzi, P. Duffau, Thomas Barnetche, Jean‐Luc Pellegrin, Jean‐François Viallard, Maya Saleh, Thierry Schaeverbeke, Patrick Legembre, Marie‐Elise Truchetet, Hélène Dumortier, Cécile Contin‐Bordes, Vanja Sisirak, Christophe Richez, Patrick Blanco
Abstract
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (T reg ) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with T reg cells via the P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) axis. Selectin interaction with PSGL-1 blocked the regulatory and suppressive properties of T reg cells and particularly follicular T reg cells by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on T reg cells induced a down-regulation of the transforming growth factor–β axis, altering the phenotype of T reg cells and limiting their immunosuppressive responses. In patients with SLE, we found an up-regulation of P- and E-selectin both on microparticles and in their soluble forms that correlated with disease activity. Last, blocking P-selectin in a mouse model of SLE improved cardinal features of the disease, such as anti-dsDNA antibody concentrations and kidney pathology. Overall, our results identify a P-selectin–dependent pathway that is active in patients with SLE and validate it as a potential therapeutic avenue.