CTLA-4 LIGATION BLOCKS CD28-DEPENDENT T-CELL ACTIVATION

CTLA-4 is a CD28 homologue believed to be a negative regulator of T ce ll function. However, the mechanism of this downregulatory activity is not well understood. The present study was designed to examine the ef fect of CTLA-4 ligation on cytokine production, cell survival, and cel l cycle progression. The results demonstrate that the primary effect o f CTLA-4 ligation is not the induction of apoptosis. Instead, CTLA-4 s ignaling blocks IL-2 production, IL-2 receptor expression, and cell cy cle progression of activated T cells. Moreover, the effect of CTLA-4 s ignaling was manifested after initial T cell activation. Inhibition of IL-2 receptor expression and cell cycle progression was more pronounc ed at late (72 h) time points after initial activation. The effects of anti-CTLA-4 mAbs were most apparent in the presence of optimal CD28-m ediated costimulation consistent with the finding that CTLA-4 upregula tion was CD28-dependent. Finally, the addition of exogenous IL-2 to th e cultures restored IL-2 receptor expression and T cell proliferation. These results suggest that CTLA-4 signaling does not regulate cell su rvival or responsiveness to IL-2, but does inhibit CD28-dependent IL-2 production.