T cell receptor clustering: a mechanism of signal transduction

Gaus K1,2

  1. EMBL Australia Node in Single Molecule Science.
  2. ARC Centre of Excellence in Advanced Molecular Imaging, University of New South Wales, Sydney, Australia.

Antigen recognition by the T cell receptor (TCR) is a hallmark of the adaptive immune system. When the TCR engages a peptide bound to the restricting major histocompatibility complex molecule (pMHC), it transmits a signal via the associated CD3 complex. How the extracellular antigen recognition event leads to intracellular phosphorylation remains unclear. We develop single-molecule localization microscopy (SMLM) approaches and novel analysis to determine how spatial organization regulates signal initiation and propagation. For example, we used SMLM data to map the organization of TCR-CD3 complexes into nanoscale clusters and to distinguish between triggered and non-triggered receptor copies. We found that only TCR-CD3 complexes in dense clusters were phosphorylated and associated with downstream signaling proteins, demonstrating that the molecular density within clusters dictates signal initiation. This lead us to propose a model in which antigen recognition is first translated into receptor clustering and then the density of receptor nanoclusters is translated into signaling. This model may explain how T cells can respond to both the affinity and dose of pMHC molecules with a common signal transduction mechanism (Pageon et al. PNAS 2016). We also developed novel FRET sensors to monitor the rate of receptor clustering (Maet al. Nat Commun 2017) and a sensor that reports membrane charges (Ma et al. Nat Biotech 2017) to understand how biophysical properties of the plasma membrane contribute to TCR signaling.