title: Minimal engagement of CD103 on cytotoxic T lymphocytes with an E-cadherin-Fc molecule triggers lytic granule polarization via a phospholipase Cgamma-dependent pathway.
abstract: Interaction of the integrin αE(CD103)β7 expressed on tumor-infiltrating lymphocytes (TIL) with E-cadherin on epithelial tumor cells is required to trigger polarized exocytosis of cytotoxic granules in TIL that elicit tumor cell lysis. In this study, we investigated the functional and signaling properties of CD103 and its individual contribution to T-cell-mediated cancer-cell killing. Our results indicated that the binding of CD103 on tumor-specific CTL to immobilized recombinant E-cadherin-Fc is sufficient to induce the polarization of cytolytic granules, whereas the degranulation of cytolytic granules also requires the coengagement of the T-cell receptor. Moreover, minimal CD103 triggering promotes the phosphorylation of the ERK1/2 kinases and phospholipase Cγ1 (PLCγ1). Inhibiting PLCγ blocks granule relocalization, decreasing T-cell receptor-mediated cytotoxicity. Thus, our results emphasize a unique costimulatory role of CD103 in tumor-specific CTL activation by providing signals that promote T-cell effector functions needed to specifically target and lyse cancer cells.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U753, Laboratoire Immunologie des tumeurs humaines: Interaction effecteurs cytotoxiques-système tumoral, Integrated Research Cancer Institute in Villejuif (IRCIV), Institut de Cancérologie Gustave Roussy (IGR), Villejuif, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Le Floc'h
authors.forename: Abdelali
authors.initials: A
authors.lastname: Jalil
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Franciszkiewicz
authors.forename: Pierre
authors.initials: P
authors.lastname: Validire
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vergnon
authors.forename: Fathia
authors.initials: F
authors.lastname: Mami-Chouaib
mesh_terms: D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D015820:Cadherins / Q000737:chemistry / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D045744:Cell Line, Tumor; D003594:Cytoplasmic Granules / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D006801:Humans; D055767:Immobilized Proteins / Q000737:chemistry / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000276:immunology*; D039001:Integrin alpha Chains / Q000276:immunology* / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D055767:Immobilized Proteins; D007141:Immunoglobulin Fc Fragments; D039001:Integrin alpha Chains; D011993:Recombinant Fusion Proteins; C091367:alpha E integrins; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051966:Phospholipase C gamma