title: Synaptic release of CCL5 storage vesicles triggers CXCR4 surface expression promoting CTL migration in response to CXCL12.
abstract: The lytic function of CTL relies on the polarized release of cytotoxic granules (CG) at the immune synapse (IS) with target cells. CTL also contain CCL5 in cytoplasmic storage vesicles (CCL5V) distinct from CG, the role of which, in regulating T cell effector functions, is not understood. Using human CD8(+) T cells specific to a lung tumor-associated Ag, we show in this article that CTL release both secretory compartments into the immune synapse with autologous tumor cells. Moreover, we demonstrate that disorganization of the T cell microtubule cytoskeleton and defects in hMunc13-4 or Rab27a abrogate CG exocytosis and synaptic secretion of the chemokine. Mechanistically, synaptic release of CCL5 cytoplasmic storage vesicles likely occurs upon their coalescence with the Rab27a-hMunc13-4 compartment and results in autocrine, CCR5-dependent induction of CXCR4 cell surface expression, thereby promoting T cell migration in response to CXCL12. We propose that CCL5 polarized delivery represents a mechanism by which CTL control immune synapse duration.
authors.affiliation: Unité U753, INSERM, Villejuif 94805, France; Institut de Cancérologie Gustave Roussy, Villejuif 94805, France; Université Paris-Sud, Orsay 91400, France;
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Franciszkiewicz
authors.affiliation: Unité U753, INSERM, Villejuif 94805, France; Institut de Cancérologie Gustave Roussy, Villejuif 94805, France; Université Paris-Sud, Orsay 91400, France;
authors.forename: Marie
authors.initials: M
authors.lastname: Boutet
authors.affiliation: Unité U753, INSERM, Villejuif 94805, France; Institut de Cancérologie Gustave Roussy, Villejuif 94805, France; Université Paris-Sud, Orsay 91400, France;
authors.forename: Ludiane
authors.initials: L
authors.lastname: Gauthier
authors.affiliation: Unité U753, INSERM, Villejuif 94805, France; Institut de Cancérologie Gustave Roussy, Villejuif 94805, France; Université Paris-Sud, Orsay 91400, France;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vergnon
authors.affiliation: Unité U753, INSERM, Villejuif 94805, France; Institut de Cancérologie Gustave Roussy, Villejuif 94805, France; Université Paris-Sud, Orsay 91400, France;
authors.forename: Kelly
authors.initials: K
authors.lastname: Peeters
authors.affiliation: Unité U753, INSERM, Villejuif 94805, France; Institut de Cancérologie Gustave Roussy, Villejuif 94805, France; Université Paris-Sud, Orsay 91400, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Duc
authors.affiliation: Département de Médecine, Institut de Cancérologie Gustave Roussy, Villejuif 94805, France;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Besse
authors.affiliation: Unité U768, INSERM, Hôpital Necker Enfants-Malades, Paris 75015, France; and Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
authors.affiliation: Unité U753, INSERM, Villejuif 94805, France; Institut de Cancérologie Gustave Roussy, Villejuif 94805, France; Université Paris-Sud, Orsay 91400, France;
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
authors.affiliation: Unité U753, INSERM, Villejuif 94805, France; Institut de Cancérologie Gustave Roussy, Villejuif 94805, France; Université Paris-Sud, Orsay 91400, France; fathia.mami-chouaib@gustaveroussy.fr.
authors.forename: Fathia
authors.initials: F
authors.lastname: Mami-Chouaib
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology*; D002633:Chemotaxis; D003594:Cytoplasmic Granules / Q000737:chemistry / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005089:Exocytosis / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D054992:Immunological Synapses; D008870:Microtubules / Q000276:immunology; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology; D020691:rab GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D000075745:rab27 GTP-Binding Proteins
chemical_list: D000951:Antigens, Neoplasm; C483024:CCL5 protein, human; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D009419:Nerve Tissue Proteins; D019718:Receptors, CXCR4; C485548:UNC13B protein, human; D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins