Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis.
Fiche publication
Date publication
juin 2021
Journal
Science translational medicine
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DUMORTIER Hélène
Tous les auteurs :
Scherlinger M, Guillotin V, Douchet I, Vacher P, Boizard-Moracchini A, Guegan JP, Garreau A, Merillon N, Vermorel A, Ribeiro E, Machelart I, Lazaro E, Couzi L, Duffau P, Barnetche T, Pellegrin JL, Viallard JF, Saleh M, Schaeverbeke T, Legembre P, Truchetet ME, Dumortier H, Contin-Bordes C, Sisirak V, Richez C, Blanco P
Lien Pubmed
Résumé
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) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with T 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 cells and particularly follicular T cells by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on T cells induced a down-regulation of the transforming growth factor-β axis, altering the phenotype of T 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.
Référence
Sci Transl Med. 2021 Jun 30;13(600):