Anton van der Merwe

Recognition of Abnormal Cells by Leukocyte Receptors

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.

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 and Cordoba et al, 2013), Simon Davis’s lab (e.g. Chang et al, 2016Chen et al, 2021 and Jenkins et at, 2023), and several other labs (e.g. James & Vale, 2012Schmidt 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 CD28NKG2DDectin-1FcyR, and FceR. As there are over 100 NTRs, we have developed a novel generic ligand system to expedite this research.

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.

Selected Publications