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 (see references 1 and 2 below). 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 PhD Prize Studentships cover full University fees, a tax free enhanced stipend of ~£24,305 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
- Cabezas-Caballero (2024) Generation of T cells with reduced off-target cross-reactivities by engineering co-signalling receptors. bioRxiv [in revisions]
- 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