Understanding and exploiting antigen discrimination by T cells
- Project No: #OxKEN-2023/4
- Intake: OxKEN 2023
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.
T cells, T cell receptor, Antigen discrimination, Co-signalling receptors, T cell therapy
Primary human T cells (isolation, culture, genetic medication, stimulation), Flow cytometry, Biophysical analysis of TCR/pMHC interactions, Quantitative data analysis, Mathematical modelling.
- Pettmann et al (2021) The discriminatory power of the T cell receptor. eLife
- 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
- Dushek & van der Merwe (2014) An induced rebinding model of T cell antigen discrimination. Current opinions in Immunology
- Lever et al (2014) Phenotypic models of T cell activation. Nature Reviews Immunology
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