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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

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.

C.R. Calvo was supported by a grant from the Coordinacion de la Investigacíon, nr. 94/5735, Ministerio Sanidad y Consuma, Madrid, Spain.

C.R. Calvo and D. Amsen contributed equally to this work.

¹ Abbreviations used in this paper: EAE, experimental allergic encephalytis; ERK2, extracellular-signal-regulated kinase 2; GST, glutathione-S-transferase; JNK, jun NH₂-terminal kinase; o/n, overnight.

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