CD95 recruits PLCγ1 to trigger a calcium response promoting Th17 accumulation in inflamed organs of lupus mice

Poissonnier, Amanda and Sanseau, Doriane and Le Gallo, Matthieu and Malleter, Marine and Levoin, Nicolas and Viel, Roselyne and Morere, Lucie and Penna, Aubin and Blanco, Patrick and Dupuy, Alain and Poizeau, Florence and Fautrel, Alain and Seneschal, Julien and Jouan, Florence and Ritz, Jerome and Forcade, Edouard and Rioux, Nathalie and Contin, Cecile and Ducret, Thomas and Vacher, Anne-Marie and Barrow, Paul A. and Flynn, Robin J. and Vacher, Pierre and Legembre, Patrick (2016) CD95 recruits PLCγ1 to trigger a calcium response promoting Th17 accumulation in inflamed organs of lupus mice. Immunity . ISSN 1097-4180 (In Press)

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Abstract

CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L, and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase Cγ1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway may be attractive therapeutic approach for SLE treatment.

Item Type: Article
Keywords: Calcium; CD95; Inflammation; Lupus; Sphingosine-1 phosphate; Th17 cell
Schools/Departments: University of Nottingham UK Campus > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Depositing User: Eprints, Support
Date Deposited: 18 Jul 2016 08:06
Last Modified: 15 Sep 2016 13:43
URI: http://eprints.nottingham.ac.uk/id/eprint/34485

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