Gangliosides and glycophorin inhibit T-lymphocyte activation.
Increased levels of gangliosides in the serum have been linked to tumour-induced immunosuppression in vivo. Both bovine brain gangliosides and human erythrocyte glycophorin were potent inhibitors of concanavalin A, periodate, and phorbol ester--ionomycin induced activation of murine T-lymphocytes. Structurally complex gangliosides were more inhibitory, while simpler glycolipids caused less inhibition. Lymphocytes exposed to these molecules for up to 24 h could still proliferate after washing. Substantial inhibition was observed only when gangliosides and glycophorin were present during the first 18 h of activation. Studies using Quin-2 showed that gangliosides did not block the initial rapid rise in cytoplasmic Ca2+ following mitogen stimulation. Interleukin-2 (IL-2) production by ganglioside- and glycophorin-treated lymphocytes was unchanged. After treatment with gangliosides for 24 h, lymphocytes proliferated normally in response to added IL-2. These results suggest that the first round of signal transduction in response to mitogen was unaffected by gangliosides. Addition of gangliosides to activated lymphocytes in the presence of IL-2 resulted in complete inhibition of proliferation. Immunosuppression by gangliosides and glycophorin thus appears to occur at the IL-2-dependent stage of proliferation and may be partially due to IL-2 binding to these molecules. However, high levels of IL-2 failed to reverse inhibition and IL-2-dependent cell lines were much less sensitive to ganglioside inhibition than T-lymphocytes, suggesting that more than one mechanism of inhibition likely exists.
Sharom
F J
FJ
Department of Chemistry and Biochemistry, University of Guelph, Ont., Canada.
Chiu
A L
AL
Ross
T E
TE
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D003864:Depression, Chemical; D005260:Female; D005732:Gangliosides / Q000494:pharmacology*; D006017:Glycolipids / Q000494:pharmacology; D006021:Glycophorins / Q000494:pharmacology*; D006028:Glycosphingolipids / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D015640:Ion Channel Gating; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D015375:Receptors, Interleukin-2 / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
D005732:Gangliosides; D006017:Glycolipids; D006021:Glycophorins; D006028:Glycosphingolipids; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D002118:Calcium