Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Accept all cookies Reject all non-essential cookies Find out more

Understanding and exploiting antigen discrimination by T cells

  • Project No: #OxKEN-2023/4
  • Intake: OxKEN 2023

Themes

1

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. Pettmann et al (2021) The discriminatory power of the T cell receptor. eLife
  2. 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
  3. Dushek & van der Merwe (2014) An induced rebinding model of T cell antigen discrimination. Current opinions in Immunology
  4. Lever et al (2014) Phenotypic models of T cell activation. Nature Reviews Immunology

CONTACT INFORMATION OF ALL SUPERVISORS

Email: omer.dushek@path.ox.ac.uk,
anton.vandermerwe@path.ox.ac.uk