SIMULTANEOUS CROSS-LINKING OF CD6 AND CD28 INDUCES CELL-PROLIFERATIONIN RESTING T-CELLS

In the present study, we showed that simultaneous ligation of the mono clonal antibodies (mAb) against CD6 and CD28 induces T-cell proliferat ion in purified resting T lymphocytes in the absence of T-cell recepto r (TCR) occupancy. No cell proliferation was observed when the mAb wer e cross-linked alone or used simultaneously in the soluble form. T-cel l proliferation mediated through CD6/CD28 is accompanied by the up-reg ulation of interleukin-2 (IL-2) mRNA and expression of IL-2 receptors on the cell surface. In the presence of IL-2-neutralizing mAb the prol iferative response of the T cells induced through CD6/CD28 was inhibit ed dose dependently. Cross-linking mAb to CD6 and CD28 alone or togeth er did not down-regulate the CD3/TCR complex. T-cell proliferation med iated through CD6/CD28 was only partially blocked by the immunosuppres sive drug, cyclosporin A (CsA), whereas anti-CD28-induced T-cell proli feration in the presence of the phorbol ester, 12-O-tetradecanoylphorb ol-13-acetate (TPA), was unaffected. In sharp contrast T-cell prolifer ation mediated by anti-CD6 in the presence of TPA was efficiently bloc ked by CsA. In addition. two protein kinase C (PKC) inhibitors, GF 109 203X and H-7 dose-dependently inhibited T-cell proliferation mediated through CD6/CD28, suggesting that PKC activation may be involved. Furt hermore, there was a marked differential dose-dependent inhibitory eff ect of the PKC inhibitors on T-cell proliferation mediated by the co-l igation of anti-CD6 or anti-CD28 in the presence of anti-CD3, with the former being more sensitive to PKC inhibition. Taken collectively, ou r results suggest that T-cell activation can occur through an antigen- independent pathway by cross-linking the accessory molecules, CD6 and CD'S, and that these two cell surface antigens may have distinct signa lling pathways.