Ganglioside inhibition of CD8+ T cell cytotoxicity: interference with lytic granule trafficking and exocytosis

• Published in: The Journal of immunology (1950) 2012-10, Vol.189 (7), p.3521-3527
• Main Authors: Lee, Hee Chul, Wondimu, Assefa, Liu, Yihui, Ma, Jennifer S Y, Radoja, Sasa, Ladisch, Stephan
• Format: Article
• Language: English
• Subjects: Animals; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - secretion; Cell Degranulation - immunology; Cell Line, Tumor; Cytoplasmic Granules - immunology; Cytoplasmic Granules - secretion; Cytotoxicity Tests, Immunologic - methods; Exocytosis - immunology; Gangliosides - pharmacology; Gangliosides - physiology; Immunological Synapses - chemistry; Immunological Synapses - immunology; Immunosuppressive Agents - pharmacology; Leukemia L1210; Lymphocyte Culture Test, Mixed - methods; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1201256

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.