Understanding and exploiting antigen discrimination by T cells

PROJECT OVERVIEW

T cells use their T-cell receptors (TCRs) to discriminate between lower-affinity self and higher affinity non-self pMHC antigens. Although this process has been widely studied, the underlying mechanisms remain unclear. In particular, it is presently unclear whether co-signalling receptors, including those routinely used for cancer immunotherapy (e.g. PD-1), only impact antigen sensitivity or also impact antigen discrimination. The objective of this project will be to investigate the contribution of various co-signalling receptors to the process of antigen discrimination by T cells and to exploit this information to improve T cell therapies as appropriate. The work will rely on primary human T cells transduced or transfected with a defined TCR to which a panel of pMHC antigens have been identified that bind with a spectrum of affinities (as described in Pettmann et al (2021) eLife). By tampering with individual co-signalling receptors, their impact on antigen sensitivity and discrimination can be quantitatively assessed and rationally exploited for improved T cell based therapies. 

KEYWORDS

T cells, T cell receptor, Antigen discrimination, Co-signalling receptors, T cell therapy

TRAINING OPPORTUNITIES

Primary human T cells (isolation, culture, genetic medication, stimulation), Flow cytometry, Biophysical analysis of TCR/pMHC interactions, Quantitative data analysis, Mathematical modelling 

KEY PUBLICATIONS

1. Lever et al (2016) Architecture of a minimal signalling pathway explains the T cell response to a 1,000,000-fold variation in antigen affinity and dose. PNAS
2. Dushek & van der Merwe (2014) An induced rebinding model of T cell antigen discrimination. Current opinions in Immunology
3. Lever et al (2014) Phenotypic models of T cell activation. Nature Reviews Immunology

CONTACT INFORMATION OF ALL SUPERVISORS

Omer Dushek - omer.dushek@path.ox.ac.uk,

Anton van der Merwe - anton.vandermerwe@path.ox.ac.uk