WORTMANNIN, A PHOSPHATIDYLINOSITOL 3-KINASE INHIBITOR, BLOCKS ANTIGEN-MEDIATED, BUT NOT CD3 MONOCLONAL ANTIBODY-INDUCED, ACTIVATION OF MURINE CD4(-CELLS() T)

Perturbation of several distinct T cell molecules, including the CD3/T CR complex, CD7, and CD28, activates phosphatidylinositol 3-kinase (PI 3-K), but a clear consensus on the role of PI3-K in T cell activation has yet to emerge, We report here that CD3 mAb-induced IL-2 production by CD4(+) T cells from D011.10 TCR-alpha beta-transgenic mice is refr actory to the potent P13-K inhibitor, wortmannin, demonstrating that a ctivation under these conditions is independent of P13-K. In marked co ntrast, wortmannin substantially inhibits IL-2 production elicited by Ag (OVA(323-339) peptide) presented by appropriate APCs (syngeneic B7( +) B cell blasts) and blocks Ag-induced differentiation of naive CD4() DO11.10 T cells into IL-4-producing cells. Wortmannin inhibits Ag-in duced conjugate formation between T cells and B7(+) B cell blasts, Bec ause T cell activation by Ag requires stable interactions with APCs, t his inhibitory effect on conjugate formation may underlie the ability of wortmannin to block Ag-induced IL-2 production and differentiation.