Role of SHP-1 in in vivo CD8+ T cell responses to antigenic stimulation

Dolton, Garry Michael 2008. Role of SHP-1 in in vivo CD8+ T cell responses to antigenic stimulation. PhD Thesis, Cardiff University.

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Abstract

The immune system has immense clinical potential for combating pathogens and tumourigenesis. More specifically, CD8+ T cells have the ability to eradicate infected and malignant cells. In light of this, the factors that may influence the speed at which antigen is detected, the magnitude of the response and the efficiency of pathogen/tumour clearance require ongoing investigation. The src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) is a negative regulator of T cell signalling pathways. Prior to this study, in vitro data had demonstrated that SHP-1 deficient CD8+ T cells possess a hyper-responsive phenotype when stimulated with cognate peptide. Therefore, the remit of this study was to establish whether this in vitro observation has an in vivo relevance. In order to explore the role of SHP-1 in an in vivo setting, CD8+ T cells from the spontaneous mouse mutant, motheaten, which lacks SHP-1 expression were utilised. Specifically, CD8+ T cells were purified from motheaten (SHP-1 deficient) and control (SHP-1 sufficient) mice and adoptively transferred to recipient mice where they could be studied. This study demonstrates that following adoptive transfer, naive SHP-1 deficient CD8+ T cells exhibit an enhanced in vivo expansion upon antigenic stimulation, which notably results in the killing of more peptide labelled target cells. Furthermore, SHP-1 deficient CD8+T cells also exhibit an enhanced memory response upon antigenic challenge. These findings suggest that modulation of SHP-1 expression may improve the efficacy of tumour immunotherapy strategies, which use antigen specific CD8+ T cells to eradicate malignant cells in tumour-bearing patients. In further support of potentially targetting SHP-1 expression in CD8+ T cells used in immunotherapy strategies, it has been importantly shown in this study that mice receiving SHP-1 deficient CD8+ T cells exhibit an enhanced protection against pulmonary tumour formation when compared to mice receiving SHP-1 sufficient CD8+ T cells.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Subjects:	Q Science > QR Microbiology > QR180 Immunology
ISBN:	9781303185403
Funders:	Tenovus
Date of First Compliant Deposit:	30 March 2016
Last Modified:	10 Jan 2018 00:54
URI:	https://orca.cardiff.ac.uk/id/eprint/55794

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