SYNERGY BETWEEN CD28 AND CD9 COSTIMULATION FOR NAIVE T-CELL ACTIVATION

Our previous study demonstrated that CD9 is expressed on most mature n aive T-cells and delivers a potent costimulatory signal that functions independently of CD28. Here, we investigated whether this CD9-mediate d signal is different from the CD28-mediated signal in the mode of cos timulation and whether both signals function synergistically for T-cel l activation. Anti-CD9 or anti-CD28 monoclonal antibody (mAb) increase d [H-3]TdR incorporation of naive T-cells in the absence of antigen-pr esenting cells (APC) when coimmobilized with submitogenic doses of ant i-CD3 mAb, The levels of costimulation induced by ligation of CD9 and CD28 were comparable. However, the costimulatory effect differed betwe en soluble anti-CD9 and CD28 mAb. A soluble form of anti-CD28 mAb coul d costimulate anti-CD3-triggered T-cells, whereas soluble anti-CD9 mAb failed to costimulate, Although anti-CD28 costimulated naive T-cells treated with phorbol myristate acetate (PMA) instead of anti-CD3 mAb, a combination of PMA plus anti-CD9 mAb could not induce T-cell activat ion. The combined costimulation of anti-CD3-triggered T-cells with ant i-CD9 and anti-CD28 mAbs resulted in strikingly enhanced [H-3]TdR upta ke and lymphokine (IL-2 and IFN-gamma) production when compared to tho se induced by each costimulation. These results suggest that CD9 and C D28 induce T-cell costimulation using different signaling pathways, th ereby inducing synergy in T-cell activation. (C) 1997 Elsevier Science B.V.