Exploring T-cell receptor function through the chemical and optical control of signal initiation
The T cell antigen receptor (TCR) triggering apparatus demonstrates the unique ability to be both highly sensitive and selective on engagement of its ligand, pMHC. These attributes are essential for T cells to detect and eliminate pathogens effectively. Although we have a reasonably comprehensive list of the proteins involved in the early signalling events, little molecular detail exists to explain how these features of TCR-mediated signalling are realised. To address this, we have used a combination of chemical and optical methods to control the initiation of TCR signalling in a quantitative manner.
We find that the ability of the TCR to discriminate between ligands is critically dependent on the recruitment and subsequent activation of ZAP70 kinase at the plasma membrane. Furthermore, the architecture of the TCR complex is primarily optimised for sensitivity, rather than signal amplification as often assumed. Our results suggest a molecular basis for ligand discrimination by the TCR in cell activation.
John did his DPhil in Oxford with Simon Davis at the IMM and then went to UC San Francisco for his postdoc in the lab of Ron Vale. He moved to University of Cambridge last year as a Wellcome Trust Sir Henry Dale Fellow, with his lab being located in the new MRC-LMB building.
Publications (in order of relevance):
JR James & RD Vale Biophysical mechanism of T cell receptor triggering in a reconstituted system Nature (2012) 487:64-9
JR James et al. Single molecule-level analysis of the subunit composition of the T-cell receptor on live T cells Proc Natl Acad Sci (2007) 104:17662-7
JR James et al. The T cell receptor triggering apparatus is composed of monovalent or monomeric proteins J Biol Chem (2011) 286:31993-2001
JR James, MI Oliveira, AM Carmo, A Iaboni & SJ Davis A rigorous experimental framework for detecting protein oligomerization using bioluminescence resonance energy transfer Nat Methods (2006) 3:1001-6