GANGLIOSIDES INHIBIT T-LYMPHOCYTE PROLIFERATION BY PREVENTING THE INTERACTION OF INTERLEUKIN-2 WITH ITS CELL-SURFACE RECEPTORS

Gangliosides are known to be actively shed from tumour cell membranes, and increased levels of circulating gangliosides may cause tumour-ind uced T-lymphocyte immunosuppression in vivo by interfering with the ac tions of interleukin-2 (IL-2). We have investigated the effect of gang liosides on the interaction of IL-2 with its cell surface receptors (I L-2R). Gangliosides inhibited IL-2-stimulated proliferation in synchro nized populations of the IL-2-dependent cell lines CTLL-2 and HT-2. Th e immunosuppressive effect was most effective when gangliosides were a dded during the first 4 hr after IL-2 stimulation, indicating that the y acted early in the IL-2 signalling pathway. Inhibition could be comp letely overcome by exogenous IL-2, suggesting that gangliosides inhibi ted growth solely by competing with IL-2R for available IL-2. In suppo rt of this proposal, gangliosides induced a concomitant dose-dependent decrease in binding of [I-125]IL-2 to high-, medium- and low-affinity IL-2R. Ganglioside-treated cells recovered their high-affinity [I-125 ]IL-2 binding after washing. The glycolipids also prevented chemical c ross-linking of [I-125]IL-2 to the p55/p75 complex, as well as to both IL-2Ralpha (p55) and IL-2Rbeta (p75) independently. A thin-layer chro matography overlay technique was used to demonstrate that IL-2 binds d irectly to gangliosides, but not to simple neutral glycolipids or acid ic lipids. Taken together, these findings indicate that gangliosides d irectly block the interaction of IL-2 with IL-2R, and may explain, in part, the immunosuppressive activities of gangliosides in vivo.