BRAIN-DERIVED GANGLIOSIDES REGULATE THE CYTOKINE PRODUCTION AND PROLIFERATION OF ACTIVATED T-CELLS

Gangliosides may regulate the activity of the immune system in vivo, p articularly within tissues such as neoplasms or the central nervous sy stem, where they are most abundant. However, the specific mechanisms b y which gangliosides modulate immune function remain incompletely unde rstood. We have characterized the effects that brain-derived gangliosi des have on specific steps of the T cell activation process in vitro, Gangliosides inhibit T cell proliferation downstream from the early ac tivation events that are bypassed pharmacologically using the combinat ion of a phorbol ester plus a calcium ionophore. These lipids block IL -2 and IFN-gamma gene transcription without inhibiting the production of IL-4 and IL-10 mRNA. This may be accounted for by the ability of ga ngliosides to prevent the activation of NF-kappa B in mitogen-stimulat ed T cells, Despite inhibiting IL-2 production, the antiproliferative effects of gangliosides are not reversed by adding supplemental IL-2 t o the culture media, This defect persists because gangliosides also bl ock the entry of activated T cells into the cell cycle, In this settin g, phosphorylation of the retinoblastoma gene product, a protein whose phosphorylation state is an important regulator of normal cell cycle progression, is prevented. These studies help to define how gangliosid es modulate T cell effector function in vitro. They also highlight the fact that certain T cell responses, namely the production of Th2-asso ciated cytokines, are not inhibited by their actions.