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Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis
- Source :
- Science Translational Medicine, Science Translational Medicine, 2021, 13 (600), pp.eabi4994. ⟨10.1126/scitranslmed.abi4994⟩, Science Translational Medicine, American Association for the Advancement of Science, 2021, 13 (600), ⟨10.1126/scitranslmed.abi4994⟩, Science Translational Medicine, American Association for the Advancement of Science, 2021, 13 (600), pp.eabi4994. ⟨10.1126/scitranslmed.abi4994⟩
- Publication Year :
- 2021
- Publisher :
- HAL CCSD, 2021.
-
Abstract
- 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 :
- 0301 basic medicine
Regulatory T cell
[SDV]Life Sciences [q-bio]
Syk
T-Lymphocytes, Regulatory
Mice
03 medical and health sciences
0302 clinical medicine
Transforming Growth Factor beta
Interferon
immune system diseases
medicine
Animals
Humans
Lupus Erythematosus, Systemic
skin and connective tissue diseases
Lupus erythematosus
biology
business.industry
General Medicine
Transforming growth factor beta
medicine.disease
3. Good health
[SDV] Life Sciences [q-bio]
030104 developmental biology
medicine.anatomical_structure
Immunology
Selectins
biology.protein
[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Antibody
business
Selectin
030215 immunology
Transforming growth factor
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 19466234 and 19466242
- Database :
- OpenAIRE
- Journal :
- Science Translational Medicine, Science Translational Medicine, 2021, 13 (600), pp.eabi4994. ⟨10.1126/scitranslmed.abi4994⟩, Science Translational Medicine, American Association for the Advancement of Science, 2021, 13 (600), ⟨10.1126/scitranslmed.abi4994⟩, Science Translational Medicine, American Association for the Advancement of Science, 2021, 13 (600), pp.eabi4994. ⟨10.1126/scitranslmed.abi4994⟩
- Accession number :
- edsair.doi.dedup.....c32f1f187cef50609414dae126a2dc43