A ROLE FOR PHOSPHATIDYLINOSITOL 3-KINASE IN GENERATING T-CELL HELP FOR B-CELL GROWTH AND DIFFERENTIATION

Evidence supporting the importance of the 3-phosphoinositide signaling pathway in lymphocyte activation is rapidly accumulating. In our stud y, we assessed the effects of two PI 3-kinase inhibitors, wortmannin a nd LY294002, on T cells as a means to analyze the role of the PI 3-kin ase-signaling pathway in the generation of T cell help for B cell grow th and differentiation. For these studies, B cells were cocultured wit h CD3-activated mitomycin C-treated T cells to induce B cell responsiv eness. Of interest, wortmannin or LY294002 pretreatment of the T cell population significantly inhibited T cell-dependent induction of B cel l proliferation and differentiation. The failure of wortmannin-treated CD3-activated mitomycin C-treated T cells to provide help in driving the differentiation of B cells to Ig-secreting cells could not be corr ected by the addition of exogenous IL-2. Further studies designed to e lucidate the mechanism by which wortmannin-treated T cells failed to p rovide B cell help indicated that wortmannin and LY294002 significantl y inhibited the induction of CD40 ligand and, to a lesser extent, inte rcellular adhesion molecule-1 expression. These results suggest that t he PI 3-kinase-signaling pathway, or other wortmannin- and LY294002 se nsitive pathways, may be important for the induction of expression of crucial interaction molecules, such as CD40 ligand, on T cells and thu s indicates that D-3 phosphoinositides play a pivotal role in regulati ng T cell-dependent B cell activation.