L-Selectin and ADAM17 in activation of virus specific T-Cells

Alanazi, Abdullah 2022. L-Selectin and ADAM17 in activation of virus specific T-Cells. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

L-selectin (CD62L) is a homing molecule expressed by leukocytes and is involved in the multistep adhesion cascade of leucocyte recruitment from the bloodstream into tissues. It was previously shown that L-selectin is re-expressed and maintained on primed virus-specific CD8+ T-cells and is required for recruitment to virus infected organs and for protective immunity. Understanding how L-selectin re-expression is regulated may have important implications for endogenous responses as well as clinical implications in adoptive T-cell therapies for viral infection treatment and cancer. It is known that ectodomain proteolytic shedding of L-selectin is regulated by ADAM17. Using an in vitro model of B-cell based peptide-MHC presentation to T-cells expressing a SLY-specific TCR revealed that L-selectin and ADAM17 expression can be detected by flow cytometry and western blotting before and after SLY engagement. Pulldown experiments revealed that L-selectin and ADAM17 are not present in a preformed complex in the cell lysate before activation and were not detectable in a complex after TCR engagement. It is therefore still unclear how ADAM17 comes to cleave L-selectin. Following SLY engagement, the released tail of L-selectin was shown to be degraded by either the proteasome or γ-secretase using specific inhibitors of both pathways. This is consistent with previous work which used the same inhibitors but different modes of T-cell activation (anti-CD3/CD28 and PMA). Furthermore, this is in-line with previous work which showed that cleavable L-selectin drives CD25 expression and clonal T-cell expansion during virus infection. The proteolysis product of the L-selectin membrane retained fragment and its function in driving T-cell expansion remains to be determined in future experiments.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	25 May 2023
Last Modified:	25 May 2023 14:09
URI:	https://orca.cardiff.ac.uk/id/eprint/159964

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