Article Dans Une Revue Science Translational Medicine Année : 2021

Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis

Pierre Vacher
Jean-Philippe Guegan
  • Fonction : Auteur
Agathe Vermorel
  • Fonction : Auteur
Emmanuel Ribeiro
  • Fonction : Auteur
Irene Machelart
  • Fonction : Auteur
Estibaliz Lazaro
Lionel Couzi
Pierre Duffau
Thomas Barnetche
Jean-Luc Pellegrin
Jean-Francois Viallard
  • Fonction : Auteur
Thierry Schaeverbeke
Patrick Legembre
Helene Dumortier

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(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.

Dates et versions

hal-03324933 , version 1 (24-08-2021)

Identifiants

Citer

Marc Scherlinger, Vivien Guillotin, Isabelle Douchet, Pierre Vacher, Andrea Boizard Moracchini, et al.. Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis. Science Translational Medicine, 2021, 13 (600), ⟨10.1126/scitranslmed.abi4994⟩. ⟨hal-03324933⟩

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