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Understanding and exploiting antigen discrimination by T cells


   Sir William Dunn School of Pathology

  Prof Omer Dushek, Prof P A van der Merwe  Friday, December 09, 2022  Competition Funded PhD Project (Students Worldwide)

About the Project

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.


Funding Notes

4 Year DPhil Prize Studentships cover full University fees, a tax free enhanced stipend of ~£20,168 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See View Website for full details and to apply.

References

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

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