title: Ganglioside inhibition of CD8+ T cell cytotoxicity: interference with lytic granule trafficking and exocytosis.
abstract: Granule exocytosis-mediated cytotoxicity by CD8(+) CTL plays a crucial role in adaptive immunity to tumors and to intracellular pathogens. This T cell effector function has been shown to be defective in various murine tumor models and in human cancer. However, factors and their mechanisms that cause inhibition of CD8(+) T cell lytic function in tumor-bearing hosts remain to be fully defined. We postulate that gangliosides, highly expressed on tumor cell membranes, actively shed into the tumor microenvironment, and having well-established immunosuppressive properties, may be such a factor. We exposed primary mouse CD8(+) CTL to gangliosides derived from three sources (tumors and normal brain). This significantly inhibited cytotoxicity-mediated by granule exocytosis, that is, cytotoxicity of alloantigen-specific and polyclonal CD8(+) CTL in vitro. These molecules did not interfere with the interaction of CD8(+) T cells with their cognate targets. Rather, they inhibited lytic granule release in response both to TCR engagement and to stimuli that induce granule release in a nonpolarized manner. At the subcellular level, confocal microscopic imaging identified inhibition of polarization of lytic granules to the immunological synapse upon target cell recognition. Thus, tumor-shed gangliosides suppress lytic activity of CD8(+) T cells by a novel mechanism, that is, inhibition of trafficking of lytic granules in response to TCR engagement, as well as by interfering with the process of granule exocytosis in CD8(+) T cells.
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Hee Chul
authors.initials: HC
authors.lastname: Lee
authors.forename: Assefa
authors.initials: A
authors.lastname: Wondimu
authors.forename: Yihui
authors.initials: Y
authors.lastname: Liu
authors.forename: Jennifer S Y
authors.initials: JS
authors.lastname: Ma
authors.forename: Sasa
authors.initials: S
authors.lastname: Radoja
authors.forename: Stephan
authors.initials: S
authors.lastname: Ladisch
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015550:Cell Degranulation / Q000276:immunology; D045744:Cell Line, Tumor; D003594:Cytoplasmic Granules / Q000276:immunology* / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods*; D005089:Exocytosis / Q000276:immunology*; D005732:Gangliosides / Q000494:pharmacology / Q000502:physiology*; D054992:Immunological Synapses / Q000737:chemistry / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007939:Leukemia L1210; D007959:Lymphocyte Culture Test, Mixed / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
chemical_list: D005732:Gangliosides; D007166:Immunosuppressive Agents; C021298:ganglioside, GD1a