Abstract
SummaryCD95 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.
Highlights
We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95 ligand (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 Cg1
Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3
Summary
Cleaved CD95L (cl-CD95L) does not trigger apoptosis, and its pathophysiological role remains unclear. Legembre and colleagues demonstrate that CD95L is expressed in SLE patient blood vessels and that after cleavage, clCD95L recruits Th17 cells to inflamed organs. In lupus-prone mice, injection of a molecule blocking cl-CD95L function alleviates signs of disease. Highlights d CD95-mediated Ca2+ response promotes endothelial transmigration of Th17 cells. Poissonnier et al, 2016, Immunity 45, 209–223 July 19, 2016 a 2016 The Author(s).
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