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Article Dans Une Revue Science Translational Medicine Année : 2021

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

Jean-Philippe Guegan
  • Fonction : Auteur
Agathe Vermorel
  • Fonction : Auteur
Emmanuel Ribeiro
  • Fonction : Auteur
Irène Machelart
  • Fonction : Auteur
Thomas Barnetche
Jean-Luc Pellegrin
Thierry Schaeverbeke

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.
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Dates et versions

hal-03436988 , version 1 (26-11-2021)

Identifiants

Citer

Marc Scherlinger, Vivien Guillotin, Isabelle Douchet, Pierre Vacher, Andréa Boizard-Moracchini, et al.. Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis. Science Translational Medicine, 2021, 13 (600), pp.eabi4994. ⟨10.1126/scitranslmed.abi4994⟩. ⟨hal-03436988⟩
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