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

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 gamma 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.
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359568
Contributor : Laurent Jonchère <>
Submitted on : Friday, September 2, 2016 - 4:18:24 PM
Last modification on : Thursday, October 8, 2020 - 3:49:32 PM

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Amanda Poissonnier, Doriane Sanseau, Matthieu Le Gallo, Marine Malleter, Nicolas Levoin, et al.. CD95-Mediated Calcium Signaling Promotes T Helper 17 Trafficking to Inflamed Organs in Lupus-Prone Mice. Immunity, Elsevier, 2016, 45 (1), pp.209--223. ⟨10.1016/j.immuni.2016.06.028⟩. ⟨hal-01359568⟩

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