Identifying signalling molecules controlling T cell antigen sensitivity and discrimination

Thesis

T cells are critical checkpoints in adaptive immunity and they are activated when their T cell surface receptor (TCR) recognises antigens presented on major histocompatibility complex (pMHC). It is well established that T cells have high sensitivity able to recognise even a single pMHC ligand and high discrimination able to respond to higher-affinity foreign pMHC but not to lower-affinity self pMHC. The mechanism(s) of antigen sensitivity and discrimination have been proposed to be dependent on a large number of molecules. These molecules are often identified by their association with TCR-proximal signalling events using different experimental assays. As a result, these conclusions rely on inference. Here, we directly quantified antigen sensitivity and discrimination in systematic experiments where different T cell molecules were modulated. Using chemical inhibitors, we identified the tyrosine kinase Lck as controlling antigen discrimination, Lck and Phospholipase Cγ (PLCγ) as controlling antigen sensitivity, and Lck, PLCγ, Calcineurin, Phosphoinisitide-3-kinase (PI3K), Protein kinase Cθ (PKCθ), Mitogenactivated protein kinase (MEK) and mammalian Target of rapamycin (mTorc) as controlling antigen efficacy (maximum response). We found no evidence that molecules Calcineurin, PI3K, PKCθ, MEK or mTorc impact antigen sensitivity or discrimination. These basic insights can improve T cell-based therapies, especially cell therapies where increasing antigen sensitivity and discrimination can improve efficacy and safety.

Authors: Andre, V

• DOI: 10.5287/ora-gogjj2bvj
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Sensitivity; T cell; Discrimination
• Subjects: Immunology