title: LFA-3 co-stimulates cytokine secretion by cytotoxic T lymphocytes by providing a TCR-independent activation signal.
abstract: T cell activation is known to depend not only on efficient antigen recognition and subsequent signaling through TCR, but also on interactions involving multiple adhesion and accessory molecules such as CD28/B7, LFA-1/ICAM-1 and LFA-3/CD2. The present study dissects the role of LFA-3/CD2 interactions in the activation of melanoma-specific CD8+ T cell clones. To this end we analyzed the influence of LFA-3 density on melanoma cells on lysis and cytokine production (TNF, IL-2, IFN-gamma) by T cells following activation by various amounts of antigenic peptides. Our results indicate that increasing LFA-3 density on melanoma cells variably affects their lysis susceptibility, but systematically and considerably enhances cytokine production by melanoma-specific cytotoxic T lymphocyte (CTL) clones. At any stimulatory antigen density, LFA-3 increased the fraction of responding cells and/or cytokine amounts produced by individual cells, without affecting TCR down-regulation. These results show that CD2 engagement increases cytokine gene activation essentially by providing to T cells a TCR-independent co-activation signal. From a practical point of view, our data demonstrate that the level of LFA-3 expressed on tumors critically affects cytokine production by specific CTL and thus the efficiency of specific immune reactions mediated by these cells.
authors.affiliation: INSERM U463 and Faculty of Sciences of Nantes, France.
authors.forename: S
authors.initials: S
authors.lastname: Le Guiner
authors.forename: E
authors.initials: E
authors.lastname: Le Dréan
authors.forename: N
authors.initials: N
authors.lastname: Labarrière
authors.forename: J F
authors.initials: JF
authors.lastname: Fonteneau
authors.forename: C
authors.initials: C
authors.lastname: Viret
authors.forename: E
authors.initials: E
authors.lastname: Diez
authors.forename: F
authors.initials: F
authors.lastname: Jotereau
mesh_terms: D000818:Animals; D018968:CD58 Antigens / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008545:Melanoma / Q000276:immunology*; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D018968:CD58 Antigens; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell