CTLA-4-mediated inhibition of early events of T cell proliferation

CTLA-4 engagement by mAbs, inhibits, while CD28 enhances, IL-2 production a nd proliferation upon T cell activation. Here, we have analyzed the mechani sms involved in CTLA-4-mediated inhibition of T cell activation of naive CD 4(+) T cells using Ab cross-linking, CTLA-4 ligation inhibited CD3/CD28-ind uced IL-2 mRNA accumulation by inhibiting IL-2 transcription, which appears to be mediated in part through decreasing NF-AT accumulation in the nuclei . However, CTLA-4 ligation did not appear to affect the CD28-mediated stabi lization of IL-2 mRNA, Further, CTLA-4 engagement inhibited progression thr ough the cell cycle by inhibiting the production of cyclin D3, cyclin-depen dent kinase (cdk)4, and cdk6 when the T cells were stimulated with anti-CD3 /CD28 and,vith anti-CD3 alone, These results indicate that CTLA-4 signaling inhibits events early in T cell activation both at IL-2 transcription and at the level of IL-2-independent events of the cell cycle, and does not sim ply oppose CD28-mediated costimulation.