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- Title
Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis.
- Authors
Scherlinger, Marc; Guillotin, Vivien; Douchet, Isabelle; Vacher, Pierre; Boizard-Moracchini, Andréa; Guegan, Jean-Philippe; Garreau, Anne; Merillon, Nathalie; Vermorel, Agathe; Ribeiro, Emmanuel; Machelart, Irène; Lazaro, Estibaliz; Couzi, Lionel; Duffau, Pierre; Barnetche, Thomas; Pellegrin, Jean-Luc; Viallard, Jean-François; Saleh, Maya; Schaeverbeke, Thierry; Legembre, Patrick
- Abstract
P-selectin as a treatment for lupus: Dysfunctional regulatory T (Treg) cells are known to be involved in the pathogenesis of systemic lupus erythematosus (SLE), but the mechanisms mediating Treg cell dysfunction are not clear. Here, Scherlinger et al. demonstrated that platelets can impair Treg cell function after forming aggregates mediated by platelet (P)–selectin expression on platelets and P-selectin glycoprotein ligand-1 (PSGL-1) expression on Treg cells. Treg cells aggregated more frequently with platelets from individuals with active SLE as compared to healthy donors. In addition, blocking the interaction between P-selectin and PSGL-1 reduced disease severity in a mouse model of SLE. Thus, the P-selectin/PSGL-1 axis may represent a therapeutic target for SLE. 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 (Treg) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with Treg 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 Treg cells and particularly follicular Treg cells by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on Treg cells induced a down-regulation of the transforming growth factor–β axis, altering the phenotype of Treg 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.
- Subjects
REGULATORY T cells; SYSTEMIC lupus erythematosus; CELL physiology; P-selectin glycoprotein ligand-1; SELECTINS; CELL aggregation; T helper cells
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 600, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abi4994