Cutting edge: extracellular signal-regulated kinases 1/2 function as integrators of TCR signal strength.

Altered signaling through the TCR is currently showing promise for immunotherapy. However, the molecular mechanisms are not completely understood. Therefore, we investigated whether varying the strength of TCR engagement in various human T cells would yield different second messenger responses. The kinetics and duration of extracellular signal-regulated kinase (ERK) activation, central to multiple cellular responses, are distinctly dependent on the T cell activation state (naive vs effector), strength of TCR cross-linking, and input from the phosphatidylinositol-3 kinase pathway, which is regulated by cytokines and growth factors. Moreover, the duration of ERK activation affects c-Fos expression, a component of the AP-1 transcription complex. Thus, the character of ERK activation, transient or sustained, acts as a signal integrator to quantify the strength of TCR engagement and direct the cellular response.