CD95-Mediated Calcium Signaling Promotes T Helper 17 Trafficking to Inflamed Organs in Lupus-Prone Mice

Poissonnier, Amanda; Sans�au, Doriane; Le Gallo, Matthieu; Malleter, Marine; Levoin, Nicolas; Viel, Roselyne; Morere, Lucie; Penna, Aubin; Blanco, Patrick; Dupuy, Alain; Poizeau, Florence; Fautrel, Alain; Seneschal, Julien; Jouan, Florence; Ritz, Jerome; Forcade, Edouard; Rioux, Nathalie; Contin-Bordes, C�cile; Ducret, Thomas; Vacher, Anne-Marie; Barrow, Paul A.; Flynn, Robin J.; Vacher, Pierre; Legembre, Patrick

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 C?1. 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 could be an attractive therapeutic approach for SLE treatment.

Citation

Poissonnier, A., Sanséau, D., Le Gallo, M., Malleter, M., Levoin, N., Viel, R., …Legembre, P. (2016). CD95-Mediated Calcium Signaling Promotes T Helper 17 Trafficking to Inflamed Organs in Lupus-Prone Mice. Immunity, 45(1), 209-223. https://doi.org/10.1016/j.immuni.2016.06.028

• Journal Article Type: Article
• Acceptance Date: May 10, 2016
• Publication Date: Jul 19, 2016
• Deposit Date: Aug 23, 2017
• Publicly Available Date: Aug 23, 2017
• Journal: Immunity
• Print ISSN: 1074-7613
• Electronic ISSN: 1097-4180
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 45
• Issue: 1
• Pages: 209-223
• DOI: https://doi.org/10.1016/j.immuni.2016.06.028
• Public URL: https://nottingham-repository.worktribe.com/output/800413
• Publisher URL: http://www.sciencedirect.com/science/article/pii/S1074761316302503