A SYNTHETIC PEPTIDE MIMICKING THE HLA-DR BETA-2-BINDING SITE FOR CD4 INHIBITS ANTIGEN-INDEPENDENT CD4(-CELL ADHESION TO B-CELLS AND CD4(+) T-CELL ACTIVATION() T)

We studied the ability of a peptide mimicking the major binding site o f HLA-DR beta 2 for CD4 (i.e. amino acids 134-148) to inhibit the adhe sion of CD4(+) T cells to B cells and ICAM-1-DR-expressing fibroblasts , as well as the proliferation of TCR-CD3-triggered CD4(+) T cells. Pe ptide DR134-148 blocked CD4(+) T cell (but not CD8(+) T cell) binding to B cells and to DR(+) ICAM-1(+) fibroblasts in a concentration-depen dent manner. A peptide composed of randomly associated identical amino acid residues had no effect. This inhibitory activity was not additiv e with the effect of an anti-CD4 antibody, peptide DR35-46 (mimicking another potential binding site of HLA-DR beta 1 to CD4) or an anti-LFA -l antibody. Adhesion of a T cell line (HUT78) expressing a mutated fo rm of CD4 unable to bind p56(lck)tyrosine kinase was not inhibited by peptide DR134-148. In addition, herbimycin A, a tyrosine kinase inhibi tor, abrogated the inhibitory activity of DR134-148. Since CD4-MHC cla ss II interactions have been shown to play no detectable role in media ting antigen-independent adhesion in this assay, peptide interactions with CD4 may trigger an off signal down-regulating LFA-l-mediated adhe sion. Indeed, adhesion of CD4(+) T cells to ICAM-1(-) fibroblasts was not inhibited by peptide DR134-148, while the same peptide inhibited a ntigen (protein-pure derivative)and anti-CD3 antibody-induced CD4 T ce ll proliferation. These findings suggest that the major sequence invol ved in the MHC class II interaction with CD4 is sufficient to induce a downstream negative regulatory signal that is mediated by p58(lck), i ndependently of antigen-specific TCR triggering.