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  • Project No: #OxKEN-2021/8
  • Intake: OxKEN

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. We have recently shown using a reductionist experimental system that the co-signalling receptors CD2 and LFA-1 can increase not only antigen sensitivity but also antigen discrimination whereas the co-receptor CD8 increases antigen sensitivity but decreases antigen discrimination. This is important because it suggests that reducing off-target responses to lower-affinity antigens may be possible without impacting on-target responses to higher-affinity antigens. 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. By tampering with individual co-signalling receptors, their impact on antigen sensitivity and discrimination can be quantitatively assessed.

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) T cells exhibit unexpectedly low discriminatory power and can respond to ultra-low affinity peptide-MHC ligands. Submitted (BioRxiv: https://www.biorxiv.org/content/10.1101/2020.11.14.382630v1)
  2. Huhn et al (2021) The discriminatory power of the T cell receptor. Submitted (BioRxiv: https://www.biorxiv.org/content/10.1101/2020.11.16.384495v1)
  3. *Trendel N, *Kruger P, Nguyen J, Gaglione S, Dushek O (2021) Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation. Science Signalling (in press, BioRxiv)
  4. 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
  5. Lever et al (2014) Phenotypic models of T cell activation. Nature Reviews Immunology

CONTACT INFORMATION OF ALL SUPERVISORS

Omer Dushek