A type of white blood cell called gamma/delta T cells can detect infections and tumours, but no one knows exactly how they do it at a molecular level. This matters because the immune system has two parallel detection systems. One—alpha/beta T cells and B cells—is well understood and forms the basis of vaccines and immunotherapies. The other—gamma/delta T cells—was discovered at the same time, in the 1980s, but remains a black box. Researchers know these cells respond to stress signals from infected or cancerous cells, but they do not know what molecules trigger that response, how those molecules appear on a cell’s surface, or how the T cell receptor physically binds to them. Without that knowledge, the entire gamma/delta system is unusable for medicine. This project aims to crack that problem by identifying the specific molecules that human gamma/delta T cells recognise, characterising how those molecules change during disease, and mapping the T cell populations that respond. The lab has already found two novel targets for these cells. If successful, this fundamental science could open a new branch of immunotherapy—one that targets stress signals common across many cancers and infections, rather than the single proteins targeted by current treatments. That is a long-term goal, but understanding the basic recognition mechanism is the necessary first step.
View original technical description
Gamma/delta T-cells have co-evolved alongside alpha/beta T-cells and B cells, and are increasingly recognized as mediating important non-redundant roles in lymphoid stress surveillance, during both pathogen infection and anti-tumour immunity. However, whereas alpha/beta T-cells and B cells are relatively well characterised, we lack the most basic knowledge of gamma/delta T-cell recognition. Indeed, despite gamma, delta, alpha and beta TCR genes being discovered contemporaneously in the 1980s, th e central issue of the role of the gamma/delta TCR in antigen recognition, remains unresolved at a molecular level. The nature of the antigens recognized by gamma/delta T-cells, and how their expression on target cells communicates signals of infection or non-microbial stress to T-cells that respond to them, remain some of the most fundamental unanswered questions in vertebrate immunology. This proposal outlines a comprehensive attempt to address these questions by defining the molecular ba sis of gamma/delta T-cell antigen recognition. Focusing predominantly on human Vdelta2-negative gamma/delta T-cells, it employs diverse molecular techniques focused on five key goals: (i)identification of gamma/delta TCR ligands (ii)characterizing their regulation/dysregulation in disease (iii)understanding how in molecular terms they are recognized and in what cellular context (iv)defining key gamma/delta T-cell populations that respond to them (v)investigating therapeutic exploitation of gamma /delta T-cell recognition. It capitalizes on studies in my laboratory that have identified two novel non-MHC ligands for human gamma/delta TCRs, facilitated by an outstanding group of UK/international collaborators. These studies should provide a major step forward in our understanding of, and ultimately in our therapeutic exploitation of, gamma/delta T-cell recognition.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know