INVOLVEMENT OF PHOSPHOINOSITIDE 3-KINASE AND RAC IN MEMBRANE RUFFLINGINDUCED BY IL-2 IN T-CELLS

IL-2 is known to play a critical role in regulating T lymphocyte proli feration. We show here that IL-2 also provokes an instantaneous and su stained membrane ruffling in cloned human or murine T cells as well as in lectin-activated peripheral blood lymphocytes. In the IL-2-induced lamellipodia, tubulin is depolymerized whereas actin is strongly poly merized, forming caps. IL-2-induced membrane ruffling is protein kinas e C (PKC) independent, as judged by the absence of effects of bisindol ylmaleimide, an efficient inhibitor of all PKC isoforms. The formation of lamellipodia by IL-2 is blocked by wortmannin and LY294002, two in hibitors of phosphoinositide 3-kinase (PI3-kinase). Moreover, expressi on in murine T cells of an inactive form of PIS-kinase inhibits IL-2-i nduced membrane ruffling, whereas expression of a constitutively activ e p110 increases the basal membrane ruffling. Rac is also involved in IL2-induced membrane ruffling since an inactive form of Rac (N17rac) b locks the IL-2-induced lamellipodia, whereas the constitutive form of Rac (Val12rac) can also lead to membrane ruffling. In the signaling ca scade, Rac is downstream of PI3-kinase since constitutive membrane ruf fling in Val12rac cells is insensitive to wortmannin. Thus, through a signaling cascade involving PI3-kinase and Rac, IL-2 can induce profou nd alterations of the T cell cytoskeleton, a phenomenon which might be of importance for T cell physiology.