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

Amanda Poissonnier; Doriane Sanseau; 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

doi:10.1016/j.immuni.2016.06.028

Journal articles

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

Amanda Poissonnier ^{1, 2} Doriane Sanseau ^{1, 2} Matthieu Le Gallo ^{1, 2} Marine Malleter ³ Nicolas Levoin ⁴ Roselyne Viel ⁵ Lucie Morere ² Aubin Penna ³ Patrick Blanco ⁶ Alain Dupuy ⁷ Florence Poizeau ⁷ Alain Fautrel ^{8, 5} Julien Seneschal ⁹ Florence Jouan Jerome Ritz Edouard Forcade ⁶ Nathalie Rioux ^{10, 3} Cécile Contin-Bordes ^{6, 11} Thomas Ducret ¹² Anne-Marie Vacher ^{13, 14} Paul A. Barrow Robin J. Flynn Pierre Vacher ¹² Patrick Legembre ¹

1 OSS - Oncogenesis Stress Signaling

2 CRLCC - CRLCC Eugène Marquis

3 Irset - Institut de recherche en santé, environnement et travail

4 Laboratoire Bioprojet

5 H2P2 - H2P2 - Histo Pathologie Hight Precision

UR1 - Université de Rennes 1, Biosit : Biologie - Santé - Innovation Technologique - Structure Fédérative de Recherche en Biologie et Santé de Rennes

6 CIRID - Composantes innées de la réponse immunitaire et différenciation

7 CHU Pontchaillou [Rennes]

8 Foie, métabolismes et cancer

9 Biothérapies des maladies génétiques et cancers

10 Service d'anatomie et cytologie pathologiques [Rennes]

11 Service d'immunologie et d'immunogénétique [Bordeaux]

12 CRCTB - Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux]

13 VINCO - Validation et identification de nouvelles cibles en oncologie

14 Université Bordeaux Segalen - Bordeaux 2

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.

Keywords : autoimmune lymphoproliferative syndrome fas gene-mutations sh3 domain protein apoptosis receptor cd95 pathway ligand death

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Journal articles

Domain :

Life Sciences [q-bio] / Ecology, environment / Health

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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359568
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Submitted on : Friday, September 2, 2016 - 4:18:24 PM
Last modification on : Wednesday, October 20, 2021 - 3:19:22 AM

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

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

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