LIGANDS OF CD4 INHIBIT THE ASSOCIATION OF PHOSPHOLIPASE C-GAMMA-1 WITH PHOSPHOINOSITIDE 3 KINASE IN T-CELLS - REGULATION OF THIS ASSOCIATION BY THE PHOSPHOINOSITIDE-3 KINASE-ACTIVITY

We have previously shown that CD4 ligands inhibit interleukin-2 (IL-2) production and T cell proliferation in human peripheral CD4(+) T lymp hocytes, in an MHC-independent way. Two major pathways implicated in T cell activation are inhibited by binding of CD4 ligands to the CD4 mo lecule, i.e. Ca2+ signaling by phospholipase C gamma 1 (PLC gamma 1), and ERK-2 activation, suggesting a p21(ras) inhibition. We have correl ated these inhibitions with the disruption of multifunctional complexe s containing PLC gamma 1, p120GAP and Sam68, induced by T cell activat ion. We report here that T cell activation through the TCR/CD3 induces an association of the phosphoinositide 3 kinase (PI3 kinase) with PLC gamma 1, both in peripheral CD4(+) T lymphocytes and the HUT-78 CD4() T cell line. PI3 kinase is present in the multifunctional complexes that we have described previously. Preincubation of human peripheral C D4(+) T cells and HUT-78 CD4(+) T cells with gp160 or a peptide analog ue of the HLA class II DR molecule precludes the association of PLC ga mma 1 with PI3 kinase. We also demonstrate, using two specific inhibit ors of PI3 kinase activity (LY294002 and wortmannin), that this activi ty plays a key role in the association of PLC gamma 1 with PIU kinase. Moreover, we demonstrate the implication of the PI3 kinase activity i n the negative signal mediated by HIV gp160 binding to CD4 molecules. We propose that the products of the PI3 kinase are important mediators of the negative signaling induced by the binding of CD4 ligands to th e CD4 molecule implicated in the regulation of the formation of multif unctional complexes.