We investigate the mechanisms by which leukocytes, such as T cells, use cell surface receptors, such as the T cell receptor (TCR), to recognise infected or otherwise abnormal cells. They do this by binding to ligands on antigen presenting and target cells. Our focus is on how the structure and binding properties of these receptor/ligand interactions contribute to their function. We apply the insights gained to improve our ability to manipulate immune responses for therapeutic purposes.
Quick links
In the KINETIC SEGREGATION mechanism CD45, which dephosphorylates the TCR and molecules recruited to it, is passively excluded from close contact zones because of its large ectodomain. This SEGREGATION enables tyrosine phosphorylation of the TCR and associated molecules by Lck. TCR/pMHC binding prevents the TCR from escaping the close-contact zone, maintains this segregation long enough to enable the downstream steps required for signalling to be completed. The slow KINETICS of TCR dissociation from pMHC provides specificity.
Matched sizes are important for membrane proximal signal integration between activating (NKG2D) and inhibitory (KIR2DL1) receptor/ligand pairs (Kohler et al 2010). Following ligand engagement inhibitory receptors recruit cytoplasmic tyrosine phosphatases (SHP-1/2). As they remain tethered to the cytoplasmic tails, SHP-1/2 can only dephosphorylate adjacent activatory receptors. This requirement for close colocalization imposes a requirement for matched receptor/ligand dimensions.
Simon Davis and I have long argued that a novel kinetic-segregation (KS) mechanism plays a critical role in signal transduction through the TCR. Originally proposed in 1996, there is now a large body of evidence for this mechanism from my lab (e.g. Choudhuri et al, 2005, Burroughs et al, 2006, Cordoba et al, 2013, and Li et al, 2024) Simon Davis’s lab (e.g. Chang et al, 2016; Chen et al, 2021 and Jenkins et at, 2023), and several other labs (e.g. James & Vale, 2012; Schmidt et al, 2016 and Razvag et al, 2018). Synthetic Chimeric Antigen Receptors (CARs) based on the TCR, which are transforming the treatment of cancer, also use the KS mechanism (Qian et al., 2022).
We have proposed that other non-catalytic tyrosine phosphorylated receptors (NTRs) or immunoreceptors also signal by the KS mechanism. We and others have published evidence supporting this for CD28, NKG2D, Dectin-1, FcyR, and FceR. As there are over 100 NTRs, we have developed a novel generic ligand system to provide evidence that 4 other families of NTRs use the KS mechanism (e.g. Barton et al 2024).
Immune recognition involves cooperation between multiple receptors, including adhesion molecules. We (e.g. Wild et al, 1999; Kohler et al 2010) and others have shown that receptor/ligand complexes often need to span the same intermembrane distance for optimal cooperation. We have proposed that this is especially critical for membrane-proximal signal integration between activatory and inhibitory NTRs, and are adapting our generic ligand system to investigate signal integration between NTRs.
In collaboration with Omer Dushek, we are investigating how to measure and optimize the sensitivity and specificity of synthetic immunoreceptors such as CARs.
Also in collaboration with Omer Dushek and others, we are investigating how the binding properties of TCR/ligand interactions influence T cell activation and the contribution of mechanical forces to these interactions.
In addition to my research I am the Director of Graduate Studies and I teach immunology to medical and biomedical science students.
2024
Ligand-induced segregation from large cell-surface phosphatases is a critical step in γδ TCR triggering.
Li, F., Roy, S., Niculcea, J., Gould, K., Adams, E.J., van der Merwe, P.A., Choudhuri, K.
Cell Rep. – 43(9):114761.
2024
Ligand requirements for immunoreceptor triggering.
Barton, M.I., Paterson, R.L., Denham, E.M., Goyette, J., van der Merwe, P.A.
Commun Biol. – 7(1):1138
2022
Mechanical forces impair antigen discrimination by reducing differences in T cell receptor off-rates.
Pettmann, J., Awada, L., Bartosz, R., Huhn, A., Faour, S., Kutuzov, M., Limozin, L., Weikl, T.R., van der Merwe, P.A., Robert, P. and Dushek, O.
EMBO J. – 42(7): e111841.
2021
Effects of common mutations in the SARS-CoV-2 Spike RBD and its ligand the human ACE2 receptor on binding affinity and kinetics.
Barton, M. I., MacGowan, S., Kutuzov, M., Dushek, O., Barton, G. J. and van der Merwe, P. A.
eLife – 10: e70658.
2021
The discriminatory power of the T cell receptor.
Pettmann, J., Huhn, A., Shah, E.A., Kutuzov, M.A., Wilson, D.B., Dustin, M.L., Davis, S.J., van der Merwe, P.A., and Dushek, O.
eLife – 10: e67092.
2019
A generic cell surface ligand system for studying cell-cell recognition.
Denham, E.M., Barton, M.I., Black, S.M., Bridge, M.J., de Wet, B., Paterson, R.L., van der Merwe, P.A. and Goyette, J.
PLoS Biology – 17(12): e3000549.
2015
Costimulation of IL-2 production through CD28 Is dependent on the size of its ligand.
Lim, H-S., Cordoba, S-P., Dushek, O., Goyette, J., Taylor, A., Rudd, C.E., and van der Merwe, P.A.
J Immunol. – 195: 5432-5439
2012
Non-catalytic tyrosine-phosphorylated receptors.
Dushek, O., Goyette, J. and van der Merwe, P.A.
Immunological Reviews – 250(1): 258-76.
ERC success for Dunn School Researchers Studying Antibiotic Resistance
September 2024
Building on the Dunn School’s rich history as the birthplace of the antibiotic era, the Isom and Stracy labs have each been awarded ERC starting grants to work on antibiotic resistance.
Dunn School Researchers Launch Innovative Spin-out: MatchBio
July 2024