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The Journal of Immunology, 1999, 162: 5813-5820.
Copyright © 1999 by The American Association of Immunologists

CTLA-4-Mediated Inhibition of Early Events of T Cell Proliferation1

Monika C. Brunner2,*, Cynthia A. Chambers*, Francis Ka-Ming Chan*, Jeff Hanke{dagger}, Astar Winoto* and James P. Allison3,*

* Howard Hughes Medical Research Institute, Cancer Research Laboratory, Department of Molecular and Cellular Biology, University of California, Berkeley, CA 94720; and {dagger} Central Division, Pfizer Inc., Groton, CT 06340

CTLA-4 engagement by mAbs inhibits, while CD28 enhances, IL-2 production and proliferation upon T cell activation. Here, we have analyzed the mechanisms involved in CTLA-4-mediated inhibition of T cell activation of naive CD4+ T cells using Ab cross-linking. CTLA-4 ligation inhibited CD3/CD28-induced 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 stabilization of IL-2 mRNA. Further, CTLA-4 engagement inhibited progression through the cell cycle by inhibiting the production of cyclin D3, cyclin-dependent kinase (cdk)4, and cdk6 when the T cells were stimulated with anti-CD3/CD28 and with 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 simply oppose CD28-mediated costimulation.




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