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Investigating the role of two activating receptors, NKG2D and NKp46, in natural killer cell education and in the development of hepatocellular carcinoma linked to chronic inflammation

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Title: Investigating the role of two activating receptors, NKG2D and NKp46, in natural killer cell education and in the development of hepatocellular carcinoma linked to chronic inflammation
Authors: Sheppard, Sam
Item Type: Thesis or dissertation
Abstract: Natural killer (NK) cells are innate lymphocytes capable of identifying infected and tumourigenic cells and eliciting a cytokine and/or cytotoxic response. NK cells contain multiple activating and inhibitory receptors that bind to ligands expressed on other cells, and responses to abnormal cells are triggered by an imbalance of NK receptor signalling in favour of activation. The NK population is phenotypically and functionally heterogeneous, allowing recognition and responses to stimuli in a broad array of diseases. Diversity within the NK cell repertoire is achieved through the processes of education and maturation, which determine the specific combination of receptors expressed on the cell surface of each NK cell and ensure self-tolerance. Inhibitory receptors play a well-established role in NK cell education, but the role of activating receptors in this process remains unclear. NKG2D and NKp46 are considered to be major NK cell activating receptors that are required for efficient clearance of neoplastic and virally infected cells. However, it is not established whether these receptors also have roles in NK cell education. The aim of the present investigation was to address this question by using a novel mouse model lacking expression of both receptors, which was generated in our laboratory by crossing mice heterozygous for the individual mutations on a C57BL/6 background. The single-knockout littermates were also used. The results indicate that NKG2D and NKp46 are not essential to NK cell development, which proceeds normally in the double-knockout (DKO) mice. With regard to NK cell education, NKG2D, but not NKp46, has a mild cell intrinsic effect on the composition of the NK cell repertoire. NKG2D also has a modest impact on NK cell maturation at the steady state. We found maturation was impaired in inflammatory contexts, suggesting that the tissue environment influences this phenotype. In parallel, the relevance of NKG2D in tumour development was investigated in a physiologically relevant carcinogen-induced model of hepatocellular carcinoma driven by inflammation. A significantly increased tumour burden was found in the presence of NKG2D. This correlated with increased infiltration of CD8+ T cells. The mechanism by which NKG2D acts to promote tumour development is not yet known, and the significance of the increase in CD8+ T cells remains to be elucidated. However, this finding strongly implies a pro-tumourigenic function for NKG2D, in addition to its known function as tumour suppressor.
Content Version: Open Access
Issue Date: Nov-2013
Date Awarded: May-2016
URI: http://hdl.handle.net/10044/1/61331
DOI: https://doi.org/10.25560/61331
Supervisor: Guerra, Nadia
Davis, Daniel
Sponsor/Funder: Biotechnology and Biological Sciences Research Council (Great Britain)
Wellcome Trust (London, England)
Department: Life Sciences
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Life Sciences PhD theses

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