CD4 LIGANDS INHIBIT THE FORMATION OF MULTIFUNCTIONAL TRANSDUCTION COMPLEXES INVOLVED IN T-CELL ACTIVATION

Ligands binding to the CD4 molecule can inhibit TCR-mediated T cell ac tivation. We have previously reported that transcription factors regul ating the expression of the IL-2 gene, NF-AT, NF-kappa B, and AP-1, ar e targets of this inhibitory effect in an in vitro model using periphe ral human CD4(+) T cells activated by a CD3 mAb. Two T cell activation pathways involved in the regulation of these transcription factors, c alcium flux and the p21(ras) pathway, were investigated as potential t argets. finding of HIV envelope glycoprotein gp160/gp120 or a CD4 mAb to the CD4(+) T cells, prior to TCR/CD3 activation, inhibited the intr acellular calcium elevation. This event strongly suggested an inhibiti on of PLC gamma 1 activity. Tyrosine phosphorylation of PLC gamma 1, i nduced by CD3 activation, was not affected, but its association with t yrosine-phosphorylated proteins, including a 62-kDa protein, was disru pted. This PLC gamma 1-associated p62 was found to be immunoreactive t o p62-Sam68 Abs. The activation-induced phosphorylation of two p21(ras ) effecters, Raf-1 and Erk2, was inhibited by the CD4 ligands, indirec tly pointing to inhibition of the p21(ras) activation pathway. In addi tion, we demonstrate that TCR activation of normal CD4(+) T cells indu ced the formation of pi 20(GAP) and PLC gamma 1-containing complexes. These complexes also contain other unidentified proteins. CD4 ligand b inding induced a defective formation of these transduction complexes. This may result in inefficient signaling, partially accounting for the inhibitory effects of the CD4 ligands on both p21(ras) and calcium-ac tivation pathways.