CD95-mediated calcium signaling promotes T helper 17 trafficking to inflamed organs in lupus-prone mice

Poissonnier, Amanda and Sanséau, 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-Bordes, Cécile and Ducret, Thomas and Vacher, Anne-Marie and Barrow, Paul A. and Flynn, Robin J. and Vacher, Pierre and Legembre, Patrick (2016) CD95-mediated calcium signaling promotes T helper 17 trafficking to inflamed organs in lupus-prone mice. Immunity, 45 (1). pp. 209-223. ISSN 1074-7613

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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 could be an attractive therapeutic approach for SLE treatment.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Identification Number: 10.1016/j.immuni.2016.06.028
Depositing User: Eprints, Support
Date Deposited: 23 Aug 2017 11:11
Last Modified: 24 Aug 2017 02:38
URI: http://eprints.nottingham.ac.uk/id/eprint/45101

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