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-kappaB family.
Highlights
The T cell receptor (TCR)1 initiates signal transduction through the intracellular regions of the CD3 and molecules via the sequence referred to as the immunoreceptor tyrosinebased activation motif [1]
ERK Activation Is Required for c-Rel Nuclear Translocation—Because lack of Shc in Jurkat cells results in partial loss of ERK activation and significant impairment of c-Rel activation and IL-2 production, we hypothesized that a high level of ERK activity is required for c-Rel nuclear translocation and IL-2 production
We examined the effect of ERK inhibition on Jurkat cells stimulated with anti-T cell antigen receptor (TCR) antibody in the presence of varying amounts of a MEK-specific inhibitor, PD98059
Summary
The T cell receptor (TCR) initiates signal transduction through the intracellular regions of the CD3 and molecules via the sequence referred to as the immunoreceptor tyrosinebased activation motif [1]. Antigenic stimulation induces Src family kinase-mediated phosphorylation of both tyrosines in immunoreceptor tyrosine-based activation motifs and creates a binding site for the cytoplasmic protein-tyrosine kinase ZAP-70 [2, 3]. Following this recruitment, ZAP-70 is activated and initiates a downstream signaling cascade. Nuclear translocation of c-Rel takes place 3– 4 h after stimulation and requires de novo synthesis of protein [6, 17, 18] This suggests that TCR-induced c-Rel nuclear translocation requires a signaling pathway distinct from the one that activates RelA. This late phase ERK activity is required for IL-2 production
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