T cell receptor clustering: a mechanism of signal transduction
- EMBL Australia Node in Single Molecule Science.
- 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.