Molecular analysis of T and NK cell recognition
Recognition of infected or otherwise abnormal cells is mediated primarily by T cells and Natural Killer (NK) cells. Indeed the recognition of pathogen-derived antigen by T cells is arguably the central event in the adaptive immune response. NK and T cell recognition occurs at the interface between two cells in direct physical contact and culminates in activation of the T or NK cells to proliferate and undertake various effector functions. These functions include killing of infected cells and deployment of other immune mechanisms. In the case of T cells this recognition requires a physical interaction between T cell antigen receptor (TCR) and pathogen-derived peptide presented on Major Histocompatibility Complex class I and II molecules (peptide-MHC). NK cell recognition involved recognition of changes in the relative expression on target cells of ligands for inhibitory and activatory NK receptors. Numerous 'accessory' cell-surface molecules (e.g. CD2, CD4, CD8, CD28) also contribute to T cell and NK cell recognition, through mechanisms which remain poorly understood.
Our research aims to understand how T and NK cell surface molecules contribute to recognition of abnormal cells. The approach we use is to characterize the basic biochemical, biophysical, structural, and cell biological properties of these molecules and their interactions. We then use this information to develop models describing their function. A key part of the work is testing these models in functional assays of T and NK cell activation.
A central problem in immunology is understanding how T cell receptor triggering occurs. In 1996 Simon Davis and I proposed the kinetic-segregation model of TCR triggering, which attempts to explain many of the features of T cell antigen recognition while taking into account the structural and ligand binding properties of the molecules involved. A major focus of my laboratory has been testing and refining this model.
We are now investigating whether other leucocyte receptors signal by the kinetic-segregation mechanism. A large number of structurally diverse receptors (>100 in humans) share key features with the TCR consistent with the kinetic-segregation mechanism. These features include small ectodomain size, surface-associated ligands, phosphorylation (and dephosphorylation) by extrinsic membrane-associated tyrosine kinases and phosphatases. We are also investigating how these receptors, which we term non-catalytic tyrosine phosphorylated receptors (NTRs), cooperate through signal integration. NTRs include several receptors families important in NK cell function (e.g. KIR, LILR, and PIR) as well as the SLAM, Siglec, CD28, C-type lectin, CD300 and SIRP families.