title: 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 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.
authors.affiliation: Centre Eugène Marquis, Rue Bataille Flandres Dunkerque, 35042 Rennes, France; INSERM ERL440-OSS, Equipe Labellisée, Ligue Contre Le Cancer, 35042 Rennes, France; Université de Rennes 1, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France.
authors.forename: Amanda
authors.initials: A
authors.lastname: Poissonnier
authors.affiliation: Centre Eugène Marquis, Rue Bataille Flandres Dunkerque, 35042 Rennes, France; INSERM ERL440-OSS, Equipe Labellisée, Ligue Contre Le Cancer, 35042 Rennes, France; Université de Rennes 1, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France.
authors.forename: Doriane
authors.initials: D
authors.lastname: Sanséau
authors.affiliation: Centre Eugène Marquis, Rue Bataille Flandres Dunkerque, 35042 Rennes, France; INSERM ERL440-OSS, Equipe Labellisée, Ligue Contre Le Cancer, 35042 Rennes, France; Université de Rennes 1, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Le Gallo
authors.affiliation: Centre Eugène Marquis, Rue Bataille Flandres Dunkerque, 35042 Rennes, France; INSERM ERL440-OSS, Equipe Labellisée, Ligue Contre Le Cancer, 35042 Rennes, France; Université de Rennes 1, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France; Biosit, Plateforme H2P2, Biogenouest, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Malleter
authors.affiliation: Bioprojet Biotech, Rue du Chesnay Beauregard, 35760 Saint-Grégoire, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Levoin
authors.affiliation: Université de Rennes 1, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France; Biosit, Plateforme H2P2, Biogenouest, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France.
authors.forename: Roselyne
authors.initials: R
authors.lastname: Viel
authors.affiliation: Centre Eugène Marquis, Rue Bataille Flandres Dunkerque, 35042 Rennes, France; INSERM ERL440-OSS, Equipe Labellisée, Ligue Contre Le Cancer, 35042 Rennes, France; Université de Rennes 1, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Morere
authors.affiliation: Université de Rennes 1, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France; INSERM U1085, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France.
authors.forename: Aubin
authors.initials: A
authors.lastname: Penna
authors.affiliation: Université de Bordeaux, CHU Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux, France; CNRS UMR 5164, 146 Rue Léo Saignat, 33076 Bordeaux, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Blanco
authors.affiliation: Université de Rennes 1, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France; Centre Hospitalier Universitaire Rennes, 2 Rue Henri Le Guilloux, 35022 Rennes, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Dupuy
authors.affiliation: Centre Eugène Marquis, Rue Bataille Flandres Dunkerque, 35042 Rennes, France; INSERM ERL440-OSS, Equipe Labellisée, Ligue Contre Le Cancer, 35042 Rennes, France; Centre Hospitalier Universitaire Rennes, 2 Rue Henri Le Guilloux, 35022 Rennes, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Poizeau
authors.affiliation: Université de Rennes 1, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France; Biosit, Plateforme H2P2, Biogenouest, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fautrel
authors.affiliation: Université de Bordeaux, CHU Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux, France; INSERM U1035, 146 rue Léo Saignat, 33076 Bordeaux, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Seneschal
authors.affiliation: Centre Eugène Marquis, Rue Bataille Flandres Dunkerque, 35042 Rennes, France; INSERM ERL440-OSS, Equipe Labellisée, Ligue Contre Le Cancer, 35042 Rennes, France; Université de Rennes 1, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Jouan
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, United States.
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.affiliation: Université de Bordeaux, CHU Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux, France; CNRS UMR 5164, 146 Rue Léo Saignat, 33076 Bordeaux, France; Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, United States.
authors.forename: Edouard
authors.initials: E
authors.lastname: Forcade
authors.affiliation: Université de Rennes 1, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France; INSERM U1085, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France; INSERM U1035, 146 rue Léo Saignat, 33076 Bordeaux, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux
authors.affiliation: Université de Bordeaux, CHU Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux, France; CNRS UMR 5164, 146 Rue Léo Saignat, 33076 Bordeaux, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Contin-Bordes
authors.affiliation: Université de Bordeaux, CHU Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux, France; INSERM U1045, 146 rue Léo Saignat, 33076 Bordeaux, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ducret
authors.affiliation: Université de Bordeaux, CHU Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux, France; INSERM U1218, Institut Bergonié, 33076 Bordeaux, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Vacher
authors.affiliation: School of Veterinary Medicine and Science, University of Nottingham, Leicestershire LE12 5RD, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Barrow
authors.affiliation: School of Veterinary Medicine and Science, University of Nottingham, Leicestershire LE12 5RD, United Kingdom.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Flynn
authors.affiliation: Université de Bordeaux, CHU Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux, France; INSERM U1218, Institut Bergonié, 33076 Bordeaux, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vacher
authors.affiliation: Centre Eugène Marquis, Rue Bataille Flandres Dunkerque, 35042 Rennes, France; INSERM ERL440-OSS, Equipe Labellisée, Ligue Contre Le Cancer, 35042 Rennes, France; Université de Rennes 1, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France; Biosit, Plateforme H2P2, Biogenouest, 2 Ave. du Prof. Léon Bernard, 35043 Rennes, France. Electronic address: patrick.legembre@inserm.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Legembre
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D059467:Transcriptome; D057705:Transendothelial and Transepithelial Migration; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D008246:Lysophospholipids; D010446:Peptide Fragments; D019014:fas Receptor; C060506:sphingosine 1-phosphate; D007371:Interferon-gamma; D051966:Phospholipase C gamma; C117399:Plcg1 protein, mouse; D013110:Sphingosine
keywords: CD95; Calcium; Th17 cell; inflammation; lupus; sphingosine-1 phosphate