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T cell antigen discrimination relies on signaling timing. Intermediate-affinity antigens cause pulsatile extracellular signal-regulated kinase (ERK) activity, with T cell activation linked to cumulative ERK signaling, revealing insights into T cell receptor dynamics.

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Area of Science:

  • Immunology
  • Cellular Signaling
  • Biophysics

Background:

  • T cell antigen discrimination is crucial for adaptive immunity.
  • T cell receptor (TCR) interaction stability with antigens dictates T cell responses.
  • Understanding the temporal dynamics of TCR signaling is key to T cell activation.

Purpose of the Study:

  • To investigate extracellular signal-regulated kinase (ERK) signaling dynamics in T cells in real-time.
  • To correlate ERK signaling patterns with antigen affinity and T cell activation.
  • To elucidate the molecular mechanisms governing TCR-induced ERK signaling.

Main Methods:

  • Real-time, single-cell imaging of TCR-antigen interactions.
  • Controlled experimental system to vary antigen affinity.
  • Analysis of ERK signaling dynamics, including frequency and amplitude.
  • Investigating the roles of LCK, MEK, MLKs, RAFs, and LAT in signaling.

Main Results:

  • Intermediate-affinity antigens induced pulsatile ERK activity at varying frequencies.
  • T cell activation correlated with the cumulative amount of ERK signaling.
  • ERK pulsing frequency was dependent on LCK activity, while MEK modulated amplitude.
  • MLKs and RAFs differentially regulated upstream signaling condensates involving LAT.

Conclusions:

  • TCR signaling exhibits complex spatiotemporal dynamics crucial for T cell activation.
  • ERK signaling frequency and amplitude are precisely controlled by upstream kinases.
  • Distinct roles of MLKs and RAFs in organizing signaling complexes highlight regulatory mechanisms.