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


Poissonnier, A, Sanseau, D, Le Gallo, M, Malleter, M, Levoin, N, Viel, R, Morere, L, Penna, A, Blanco, P, Dupuy, A et al (show 14 more authors) (2016) CD95-Mediated Calcium Signaling Promotes T Helper 17 Trafficking to Inflamed Organs in Lupus-Prone Mice. Immunity, 45 (1). pp. 209-223.

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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
Uncontrolled Keywords: Calcium, CD95, inflammation, lupus, Sphingosine-1 phosphate, Th17 cell
Depositing User: Symplectic Admin
Date Deposited: 27 Sep 2016 10:16
Last Modified: 19 Jan 2023 07:30
DOI: 10.1016/j.immuni.2016.06.028
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3003322
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