CTLA-4 ligation blocks CD28-dependent T cell activation.

TLDR

CTLA‑4, a CD28 homologue, is thought to negatively regulate T‑cell function, but its precise downregulatory mechanism remains unclear. The study aimed to determine how CTLA‑4 ligation affects cytokine production, cell survival, and cell‑cycle progression in activated T cells. CTLA‑4 ligation suppresses IL‑2 production, IL‑2 receptor expression, and cell‑cycle progression without inducing apoptosis, an effect that intensifies after initial activation, is most evident with strong CD28 costimulation, and can be rescued by exogenous IL‑2, indicating that CTLA‑4 inhibits CD28‑dependent IL‑2 signaling rather than cell survival.

Abstract

CTLA-4 is a CD28 homologue believed to be a negative regulator of T cell function. However, the mechanism of this downregulatory activity is not well understood. The present study was designed to examine the effect of CTLA-4 ligation on cytokine production, cell survival, and cell cycle progression. The results demonstrate that the primary effect of CTLA-4 ligation is not the induction of apoptosis. Instead, CTLA-4 signaling blocks IL-2 production, IL-2 receptor expression, and cell cycle progression of activated T cells. Moreover, the effect of CTLA-4 signaling was manifested after initial T cell activation. Inhibition of IL-2 receptor expression and cell cycle progression was more pronounced 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-mediated costimulation consistent with the finding that CTLA-4 upregulation was CD28-dependent. Finally, the addition of exogenous IL-2 to the cultures restored IL-2 receptor expression and T cell proliferation. These results suggest that CTLA-4 signaling does not regulate cell survival or responsiveness to IL-2, but does inhibit CD28-dependent IL-2 production.