Avidity-Dependent Metabolic Imprinting of Anti-Viral T Cell Responses

This PhD project explores the immune response to Epstein-Barr virus (EBV), focusing on the metabolism of EBV antigen-specific T cells.
Long-lived memory T cells are essential to the surveillance and control of persistent viral infections, enabling a life-long balance between the host's immune response and the virus. Understanding the mechanisms by which T cells control EBV is important for developing future therapies against EBV-associated diseases.
T cells interact with target cells via their T cell receptor (TCR). Each T cell carries a unique TCR that is specific to a particular component of a virus or pathogen. How well a T cell is able to respond upon TCR activation is termed the functional avidity. However, little is known about the differences between individual virus-specific T cells, and how these may be influenced by the diversity of TCRs found across these populations. This fundamental link between TCR diversity and function, is important for the development of T cell-based therapies, where it is essential to be using T cells with the best potential.
This project uses EBV as a model system for exploring virus-specific T cell responses and their metabolism. Firstly, we will use MHCI tetramer reagents to identify virus-specific T cells. Tetramer staining will be combined with various flow cytometry based metabolic characterisation assays to determine the functional potential of different T cells. Secondly, we will isolate T cells specific for EBV and characterise their TCR repertoire and functional avidity. We will then compare their expression of key signalling molecules downstream of the TCR to understand how the avidity of the TCR impacts the function of the T cells. T cell metabolic profiles will also be compared by extracellular flux analysis (Seahorse).
Overall, understanding how TCR avidity influences the ability of T cells to function is important to optimise the use of T cells for therapies against EBV-associated diseases.