Regulation of interleukin 2-dependent growth responses by glycosylphosphatidylinositol molecules

Abstract

The molecular mechanism of signal transduction through the interleukin 2 (IL-2) receptor remains an enigma. Glycosylphosphatidylinositol (GPI) lipids were investigated as one component of this process. IL-2 stimulated the rapid (30 sec) loss of greater than 50% of GPI in the IL-2-dependent T-cell line CTLL-2. Half-maximal GPI loss was detected at 40 pM IL-2, coincident with the EC50 (20 pM) for IL-2-induced proliferation of this cell line. This effect was specifically inhibited by antibodies that bind either IL-2 or the IL-2 receptor. The loss of GPI was mirrored by the accumulation of both polar inositolphosphoglycan (IPG) and diacylglycerol lipid fragments within cells. Increases in lipids were initially restricted to myristoyl diacylglycerol but were followed by the accumulation of myristoyl phosphatidic acid. These results are indicative of IL-2-dependent hydrolysis of GPI in T cells. The biological relevance of this hydrolysis was demonstrated by synergism of purified IPG with IL-2 in T-cell proliferation responses. The inclusion of IPG (0.1 microM) in determinations of IL-2-dependent CTLL-2 growth shifted the EC50 from 20 to 7 pM IL-2. IPG had no effect on either the number or affinity of IL-2 receptors; therefore, half-maximal CTLL-2 proliferation was obtained at less than 10% IL-2 receptor occupancy. These results demonstrate that GPI lipids are an important component of the biological response to IL-2.