J. Exp. Med., Volume 186, Number 10, November 17, 1997 1645-1653

Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) Interferes with Extracellular Signal-regulated Kinase (ERK) and Jun NH₂-terminal Kinase (JNK) Activation, but Does Not Affect Phosphorylation of T Cell Receptor  and ZAP70

By Concepcion Revilla Calvo, Derk Amsen, and Ada M. Kruisbeek

From the Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an important regulator of T cell homeostasis. Ligation of this receptor leads to prominent downregulation of T cell proliferation, mainly as a consequence of interference with IL-2 production. We here report that CTLA-4 engagement strikingly selectively shuts off activation of downstream T cell receptor (TCR)/CD28 signaling events, i.e., activation of the microtubule-associated protein kinase (MAPKs) ERK and JNK. In sharp contrast, proximal TCR signaling events such as ZAP70 and TCR- chain phosphorylation are not affected by CTLA-4 engagement on activated T cells. Since activation of the ERK and JNK kinases is required for stimulation of interleukin (IL)-2 transcription, these data provide a molecular explanation for the block in IL-2 production imposed by CTLA-4.

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