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

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 VacherPaul A. Barrow, Robin J. Flynn, Pierre Vacher, Patrick Legembre

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)209-223
Number of pages15
JournalImmunity
Volume45
Issue number1
DOIs
Publication statusPublished - 19 Jul 2016
Externally publishedYes

Keywords

  • Calcium
  • CD95
  • inflammation
  • lupus
  • sphingosine-1 phosphate
  • Th17 cell

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