[Research Articles] Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis

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.

Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: Scherlinger, M., Guillotin, V., Douchet, I., Vacher, P., Boizard-Moracchini, A., Guegan, J.-P., Garreau, A., Merillon, N., Vermorel, A., Ribeiro, E., Machelart, I., Lazaro, E., Couzi, L., Duffau, P., Barnetche, T., Pellegrin, J.-L., Viallard, J.-F., Saleh Tags: Research Articles Source Type: research