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The pattern and functional consequence of Killer Immunoglobulin-like Receptor expression on T cells.

Chagoury, Odette Louise (2009)
Ph.D. thesis, University of Birmingham.

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Abstract

Killer immunoglobulin-like receptors (KIRs) are a family of proteins expressed on human natural killer cells and a subset of T cells. Several inhibitory KIRs have been shown to recognise MHC class I molecules (predominantly HLA-C), with their engagement preventing target cell lysis. The ligand(s) and function(s) of activating KIRs, however, are less well characterised. Genetic studies of the association of KIRs with disease have identified an association with viral infections and autoimmune disease and this implicates that these proteins are important in human health. This thesis was concerned with an investigation of the factors that determine KIR expression on lymphocytes, and how this might influence the cellular functional response. In my initial work I produced soluble recombinant forms of activating and inhibitory KIRs and studied the biophysical interaction of these proteins with HLA-C molecules. I saw some evidence that KIR2DS2 binds to the HLA-C group 1 allele HLA-Cw*0702, supporting the idea that HLA-C alleles are a true ligand for stimulatory KIRs. I then went on to make a detailed 11 colour flow cytometric analysis of the expression of KIR proteins in healthy individuals. I was able to show that total, and individual, KIR protein expression was correlated and defined a pattern of dominance on lymphoid subsets. I then went on to study the distribution of KIR expression on discrete memory T cell subsets and showed that they were found predominantly on late differentiating CD45RA+ T cells. Interestingly there was also considerable expression on central memory CD8+ T cells although the biological basis for this is unclear. I demonstrated that age and CMV infection have a marked effect on KIR expression and I speculate on the reason for this. Finally I studied KIR expression on CMV-specific T cell clones in order to undertake a functional analysis of the consequence of KIR expression. I observed that KIR expression increased when cells were cultured in vitro but I could not detect any difference in cytokine production or cytotoxicity between KIR+ and KIR- cells. My work has contributed to the literature on KIR biology in relation to lymphoid cells and will have direct relevance to a number of clinical studies.

Type of Work:Ph.D. thesis.
Supervisor(s):Moss, Paul (Professor) and Briggs, David (Dr)
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Cancer Studies
Subjects:RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
ID Code:398
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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