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A study of MHC class I binding viral and host derived peptides and natural killer cell function

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Title: A study of MHC class I binding viral and host derived peptides and natural killer cell function
Authors: Cheent, Kuldeep
Item Type: Thesis or dissertation
Abstract: Natural killer (NK) cells are a key component of innate immunity and have been implicated in determining the outcome of HCV infection in both genetic and functional studies. The last two decades have seen significant advances in the understanding of NK cell regulation with the discovery of a multitude of activating and inhibitory receptors. CD94:NKG2A operates in tandem with the polymorphic killer cell immunoglobulin-like receptors (KIR) and Ly49 systems to inhibit NK cells, however it is not clear as to the benefits of having two distinct inhibitory receptor:ligand systems. Down regulation or modification of MHC class I expression is a key feature of NK cell recognition of virus infected cells. However, viruses can subvert this mechanism of NK cell surveillance by encoding peptides that can bind to MHC class I. The aim of this thesis is to further our understanding of the interaction between viral and host derived MHC class I binding peptides and their effect on NK cell inhibition. By using an MHC deficient cell line, we have shown that HCV core35-44 peptide is capable of enhancing cell surface expression of MHC class I (HLA-C and HLA-E). Although this peptide stabilises HLA-E, the HLA-E:HCV core35-44 complex alone is insufficient to inhibit at NKG2A positive NK cells. However, in the presence of HLA-E binding MHC class I signal peptides, HCV core35-44 has a synergistic effect in suppressing the NKG2A+ NK cell population. Peptides derived from other viruses such as EBV and HIV, and the stress related peptide derived from heat shock protein 60 also augment inhibition of NKG2A+ NK cells, but only when in the presence of MHC class I signal peptides. This augmentation is caused by recruitment of the non-signalling CD94 molecule to the immune synapse in the absence of its inhibitory signalling partner NKG2A. Thus CD94 can function independently as an enhancer of inhibition. The augmentation of inhibition of CD94:NKG2A by non-inhibitory peptides, contrasts with antagonism of inhibition of KIR by low affinity peptide:MHC complexes. We also show that KIR+ and NKG2A+ NK cells respond with differing stoichiometries to MHC class I down-regulation. Thus peptide selectivity and MHC class I sensitivity of natural killer cell receptors provides a rationale for the evolution of two distinct inhibitory systems for MHC class I.
Content Version: Open Access
Issue Date: Jul-2013
Date Awarded: Jan-2014
URI: http://hdl.handle.net/10044/1/19024
DOI: https://doi.org/10.25560/19024
Supervisor: Khakoo, Salim
Purbhoo, Marco
Sponsor/Funder: Wellcome Trust (London, England)
Funder's Grant Number: WT087806MA
Department: Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses

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