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Title: Regulation of T cell activation
Author: Demetriou, Philippos
ISNI:       0000 0004 7430 7320
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Recognition of a cognate peptide-MHC molecule by its T cell receptor (TCR) triggers a critical cascade of protein re-organisation and clustering at the cell interface. This results in the formation of the immunological synapse (IS), concurrent with and influencing T cell activation. The glycoprotein CD2 with its ligand CD48 (mouse) or CD58 (human) has been shown to act as an important adhesion/co-stimulatory molecule influencing the T cell activation. While initial analysis of the knockout mouse revealed redundancy with LFA-1 and CD28, activity of this pathway has been correlated with enhanced pathogen clearance and autoimmunity in humans, renewing interest. Earlier analysis of CD2 dynamics in Jurkat cells revealed formation of large domains that display centralization similar to the TCR and co-stimulatory receptors like CD28. We have found that ligated CD2 displays a more complex behaviour in previously uncharacterized later stages of IS maturation in primary mouse and human CD4+ T cells. We observed that the CD2-CD58 complexes colocalised with TCR/pMHC microclusters during the formation of the mature IS, characterized by the central supramolecular activation cluster (cSMAC) where TCR signaling is terminated. Upon formation, the CD2-CD58-rich plaques moved outwards to form a 'corolla', a segmented ring outside the LFA-1-ICAM-1 peripheral SMAC (pSMAC). This 'corolla' is enriched in downstream active signalling molecules. We found that the CD2 'corolla' also brings with it other co-stimulatory receptors like ICOS and CD28. We suggest that CD2 rescues TCR and costimulatory signalling complexes that are destined for termination in the cSMAC to a peripheral site where signalling can be sustained, leading to enhanced signal integration. Interestingly, investigation of the classical co-inhibitory receptor PD-1, revealed that PD-1 and CD2 corolla can be segregated under specific conditions but can also colocalise in the periphery of the IS; preliminary data suggests that this is dependent on the expression levels of PD-1. Overall, our results suggest that the expression levels of these co-stimulatory/inhibitory receptors can influence their localisation dynamics within the IS. Most importantly, CD2 expression levels are one of the key factors controlling corolla formation. Our results suggest that the expression levels of the co-stimulatory/inhibitory receptors have functional implications in the IS. Finally, we have investigated the levels of CD2 and PD-1 in the tumour microenvironment where tumour-infiltrating lymphocytes (TILs) are failing to stop tumour growth. Our preliminary data in small cohort of eight colorectal cancer patients were surgical specimens were acquired demonstrate high levels of PD-1 and low expression of CD2 in CD8+ TILs compared to CD8+ T cells found in normal tissue adjacent to the tumour or in peripheral blood CD8+ T cell compartment of healthy individuals. In summary, we are proposing that CD2 acts both as a classic costimulator with strong expression the ability to enhance activation of Src famly kinases and as an organiser or co-stimulatory/inhibitory signalling in the IS.
Supervisor: Bowness, Paul ; Dustin, Michael L. Sponsor: Kennedy Trust Studentship
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available