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

Poissonnier, Amanda; Sanséau, 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, Cécile; Ducret, Thomas; Vacher, Anne-Marie; Barrow, Paul A.; Flynn, Robin J.; Vacher, Pierre; Legembre, Patrick

Authors

Amanda Poissonnier

Doriane Sanséau

Matthieu Le Gallo

Marine Malleter

Nicolas Levoin

Roselyne Viel

Lucie Morere

Aubin Penna

Patrick Blanco

Alain Dupuy

Florence Poizeau

Alain Fautrel

Julien Seneschal

Florence Jouan

Jerome Ritz

Edouard Forcade

Nathalie Rioux

Cécile Contin-Bordes

Thomas Ducret

Anne-Marie Vacher

Paul A. Barrow

Robin J. Flynn

Pierre Vacher

Patrick Legembre



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.

Journal Article Type Article
Publication Date Jul 19, 2016
Journal Immunity
Print ISSN 1074-7613
Electronic ISSN 1097-4180
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 45
Issue 1
Pages 209-223
APA6 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
DOI https://doi.org/10.1016/j.immuni.2016.06.028
Publisher URL http://www.sciencedirect.com/science/article/pii/S1074761316302503
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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