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A Novel ERK-dependent Signaling Process That Regulates Interleukin-2 Expression in a Late Phase of T Cell Activation*

T. Koike,H. Yamagishi,Yasue Hatanaka,A. Fukushima,Jing-wen Chang,Yan Xia,M. Fields,P. Chandler,M. Iwashima

Published 2003 in Journal of Biological Chemistry

ABSTRACT

Engagement of the T cell antigen receptor (TCR) rapidly induces multiple signal transduction pathways, including ERK activation. Here, we report a critical role for ERK at a late stage of T cell activation. Inhibition of the ERK pathway 2–6 h after the start of TCR stimulation significantly impaired interleukin-2 (IL-2) production, whereas the same treatment during the first 2 h had no effect. ERK inhibition significantly impaired nuclear translocation of c-Rel with a minimum reduction of NF-AT activity. Requirement for sustained ERK activation was also confirmed using primary T cells. To induce sustained activation of ERK, T cells required continuous engagement of TCR. Stimulation of T cells with soluble anti-TCR antibody resulted in activation of ERK lasting for 60 min, but failed to induce IL-2 production. In contrast, plate-bound anti-TCR antibody activated ERK over 4 h and induced IL-2. Furthermore, T cells treated with soluble anti-TCR antibody produced IL-2 when phorbol 12-myristate 13-acetate, which activates ERK, was present in the culture medium 2–6 h after the start of stimulation. Together, the data demonstrate the presence of a novel activation process following TCR stimulation that requires ERK-dependent regulation of c-Rel, a member of the NF-κB family.

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