Anton van der Merwe
Recognition of abnormal cells by leukocyte receptors
The group studies the mechanisms by which leukocytes, such as T cells, use cell surface receptors to recognise infected or otherwise abnormal cells. The T cell receptor (TCR) plays a major role in this process by probing the surfaces of cells for the presence of 'foreign' peptides presented on MHC molecules in a peptide-MHC (pMHC) complex. A major focus of our work is to understand how the binding of TCRs to foreign pMHC leads to T cell activation. The first step in TCR signal transduction following ligand engagement is tyrosine phosphorylation of the TCR/CD3 complex, which we term triggering. Simon Davis and I have proposed a new mechanism of TCR triggering, termed the kinetic-segregation model. It postulates that TCR binding to pMHC segregates the TCR, and the tyrosine kinases that phosphorylate it, from tyrosine phosphatases with large extracellular domains such as CD45 and CD148.
A large number of leukocyte cell-surface receptors share key similarities with the TCR, suggesting that they signal by the same kinetic-segregation mechanism. These proteins, which comprise the largest group of leukocyte surface molecules, are termed non-catalytic tyrosine phosphorylated receptors (NTRs) or immunoreceptors. Over 100 NTRs have been described. One focus of our work is to investigate whether other NTRs trigger by the kinetic-segregation mechanism.
Leukocytes express multiple NTRs, some of which are activating, like the TCR, while some are inhibitory. We are investigating the mechanisms by which activating and inhibitory NTRs integrate their signals when they engage ligands. We have proposed that intimate-co-localization at the cell-cell interface is critical for signal integration, and that NTR/ligand complexes need to span similar intermembrane distances to colocalize.
A full list of publications and citations can be viewed on Google Scholar.
Scientific Reports 6: 1–11
Biophysical J 110:1896-1906
Cell 164: 128-140
J Immunol 195: 5432-5439
Blood 121: 4295-302.
Immunol Rev 250: 258-76.
Immunity 32: 163-74.
Nature 436: 578-82.