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Title: Positive and negative regulation of natural killer (NK) cell signalling pathways in function and development
Author: Hampshire, D. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2010
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The class 1 PI3K enzyme family includes the catalytic isoforms p110γ, p110σ, and p110β. The role of p110β in NK cell biology is unknown. Using a p110β knockout (KO) mouse strain we demonstrate that NK cell development is p110β-independent. We show that IL-2-activated NK cells from p110β KO mice are able to kill YAC-1 and RMA-S target cells as efficiency as wild-type (WT) NK cells. Moreover, we demonstrate that p110β is a dispensable positive regulator for NKG2D-dependent killing. By contrast, NK cell Fc-mediated killing is partially dependent on p110β. Our hypothesis is that an increase in Src kinase activity might take place in NK cells following the elimination of Csk, resulting in an enhanced cellular response even at low levels of stimulation. A transgenic mouse has been developed where the Csk gene is flanked by LoxP (floxed) sites. Crossing Csk floxed transgenic mice with transgenic mice expressing Cre recombinase under the control of the human CD2 gene (hCD2-iCre) enables the deletion of the Csk gene in a tissue-specific manner. Intracellular staining for Csk demonstrates that hCD2-iCre deletes the floxed gene in approximately 30% of splenic NK cells, whereas the vast majority of B and T cells show evidence of iCre mediated recombination driven by hCD2. There is no significant difference between the number of splenic NK cells from Csk KO and CD2-iCre ROSA26 (WT) mice. However, the number of mature NK cells from the bone marrow of Csk KO mice is lower than that of WT. Unexpectedly, Csk-deficient primary NK cells from the spleen show significantly reduced cytotoxicity against YAC-1 target cells. This finding suggests that Csk plays a positive role in NK cell activation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available