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Title: Nanometre-scale organisation of the inhibitory human natural killer cell receptor KIR3DL1 and its HLA class I ligands
Author: Barthen, Charlotte Celine
ISNI:       0000 0004 7427 6798
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Natural killer (NK) cells express an array of activating and inhibitory receptors, which enable the detection of stress-induced markers and ‘self’ human leukocyte antigen (HLA) class I molecules on target cells. The distribution of these receptors at the cell surface is thought to be important for signal integration at the immune synapse. Killer-cell immunoglobulin-like receptors (KIR) and HLA class I proteins are highly polymorphic. In particular, allelic variation affecting the expression and function of the inhibitory receptor KIR3DL1 and its HLA class I ligands, can influence HIV infection outcome. It is not known, however, if genetic variation can affect the organisation of KIR and HLA proteins at the cell surface and at the NK-cell immune synapse. Here, single-molecule localisation microscopy was used to investigate the spatial distribution of KIR3DL1 and HLA class I proteins within the plasma membrane. HLA class I proteins were relatively evenly distributed at the nanometre-scale, with fewer than 5% of molecules forming clusters in unstimulated primary B cells. In contrast, over half of KIR3DL1 receptors were constitutively arranged in clusters sized 4064 ± 384 nm2, at the surface of resting NK cells. Receptor ligation induced the reorganisation of KIR3DL1, resulting in the formation of larger and denser clusters. Interestingly, the extent of these changes varied for different alleles of KIR3DL1, suggesting that genetic variability may affect KIR3DL1 recruitment at the NK-cell synapse. Allelic variation did not influence the constitutive organisation of KIR and HLA proteins, when expressed at the same level. However, their nanoscale distribution was influenced by cell surface levels; at higher expression levels, HLA class I clustering decreased, whereas the number of KIR3DL1 clusters increased when expressed at higher levels. These results demonstrate the distinct nanoscale organisation of KIR3DL1 and HLA class I molecules. Moreover, factors that influence their expression, including genetic variation, may have an important impact on the distribution of KIR3DL1 and HLA class I proteins at the cell surface.
Supervisor: Davis, Daniel ; Selkirk, Murray Sponsor: Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral