The role of glycosphingolipids in natural immunity. gangliosides modulate the cytotoxicity of natural killer cells

Abstract

Incubation of gangliosides with natural killer (NK) cells from various sources was found to inhibit NK activity in vitro whereas incubation of the same gangliosides with human or mouse lymphoma cells prior to their exposure to NK effectors resulted in a sharp increase in the NK sensitivity of the tumor cells. These effects depended on the oligosaccharide structure of the gangliosides and on the origin of the NK effector cells. The lysis of YAC cells by mouse splenocytes or of MOLT-4 cells by NK cells isolated from the peripheral blood of Syrian hamsters or humans was inhibited most strongly by pre-incubation of the effector cells with gangliosides GM3 and GD3 which are known to be elevated in the serum of tumor-bearing hosts. It is suggested that target cell-associated gangliosides may function as target structures recognized by NK cells while serum gangliosides may contribute to the inhibition of NK cells during tumor development and thus help the tumor to escape NK surveillance.

Modulation of Growth Factor Signaling by Gangliosides: Positive Or Negative?

“…Furthermore, gangliosides are overexpressed by tumor cells and shed into the tumor microenvironment. Tumor gangliosides can both influence the behavior of the tumor cells that produce them and can alter biological functions of target cells to which shed gangliosides bind.Gangliosides, which exist in glycosphingolipid-enriched domains (Hakomori et al, 1998), have several important biological properties, including potent immunosuppressive activity (Bergelson et al, 1989;Grayson and Ladisch, 1992;Ladisch et al, 1983;Lu and Sharom, 1996), proangiogenic activity (Alessandri et al, 1987;Manfredi et al, 1999;Zeng et al, 2000), and enhancement of growth factor-mediated fibroblast and vascular endothelial cell proliferation (Lang et al, 2001;Li et al, 2001;Rusnati et al, 2002). These findings have in turn led to interest in the role of gangliosides in the modulation of cell signaling, resulting in NIH Public Access studies spanning a wide range of growth factors, cell types, ganglioside species, and experimental conditions.…”

Biosynthesis and excretion of gangliosides by the isolated perfused rat liver

“…Recoveries of the total mixed ganglioside standard added to one aliquot of each perfusate, liver and bile sample, prior to the purification procedure were 65 -73Y0 ; recoveries of individual ganglioside components did not differ. (8), GMt (7), GM' (6) , G D 3 ( 5 ) , GD,, (4). (2), GQ + origin (1).…”

Ganglioside Inhibition of CD8+ T Cell Cytotoxicity: Interference with Lytic Granule Trafficking and Exocytosis

“…Importantly, they are actively shed from the membranes of these tumor cells, as first discovered in the murine YAC lymphoma (5) and confirmed in numerous different human tumors, such as neuroblastoma (6), melanoma (7), leukemia (8), and renal cell carcinoma (9). A spectrum of immunosuppressive effects of exogenously added gangliosides has been described, including reversible inhibition of APC function (10), T cell proliferation (5), cytokine production (11), NK cell function (12), and B cell Ab production (13). Some specific cellular mechanisms of tumor ganglioside activity on T cells include degradation of NF-kB (14), influencing Th differentiation (11,15,16) and causing apoptosis (17,18).…”

“…Some specific cellular mechanisms of tumor ganglioside activity on T cells include degradation of NF-kB (14), influencing Th differentiation (11,15,16) and causing apoptosis (17,18). Cytotoxic activity (12,19), which complements the other mechanisms of T cell activity involved in the antitumor immune responses summarized above, is also inhibited but the mechanism of ganglioside inhibition is unknown. In this study we assessed the individual steps in the process of granule exocytosismediated cytotoxicity of CD8 + T lymphocytes.…”