Role for lipid rafts in regulating interleukin-2 receptor signaling

Lipid rafts are plasma membrane microdomains characterized by a unique lipi d environment enriched in gangliosides and cholesterol, leading to their in solubility in nonionic detergents. Many receptors are constitutively or ind ucibly localized in lipid rafts, which have been shown to function as platf orms coordinating the induction of signaling pathways. In this report, the first evidence is provided for a role of these lipid microdomains in regula ting interleukin-2 receptor (IL-2R) signaling. It is demonstrated that anti body- or ligand-mediated immobilization of components of lipid rafts, glyco syl-phosphatidyl-inositol-anchored proteins, and the GM1 ganglioside, respe ctively, inhibit IL-2-induced proliferation in T cells. IL-2R alpha is show n to be constitutively enriched in rafts and further enriched in the presen ce of immobilized anti-Thy-1. In contrast, IL-2R beta and IL-2R gamma, as w ell as JAK1 and JAK3, are found in soluble membrane fractions, and their lo calization is not altered by anti-Thy-1. IL-2-mediated heterotrimerization of IL-2R chains is shown to occur within soluble membrane fractions, exclus ively, as is the activation of JAK1 and JAK3. As predicted by these results , the disruption of lipid raft integrity did not impair IL-2-induced signal ing. Thus, the sequestration of IL-2Ra within lipid microdomains restricts its intermolecular interactions and regulates IL-2R signaling through imped ing its association with IL-2R beta and IL-2R gamma. (C) 2001 by The Americ an Society of Hematology.