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Title: Mechanisms of natural killer cell activation by Plasmodium falciparum-infected erythrocytes and influenza vaccine
Author: Sherratt, S. R.
ISNI:       0000 0004 7970 5758
Awarding Body: London School of Hygiene & Tropical Medicine
Current Institution: London School of Hygiene and Tropical Medicine (University of London)
Date of Award: 2019
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Natural Killer (NK) cells are immune effector cells capable of responding to infected cells through cytotoxic activity and production of pro-inflammatory cytokines. In recent years there has been increasing interest in studying how vaccine- or pathogen-induced antibodies promote NK cell responses to pathogens through the immunoglobulin G receptor CD16. The initial work described in this thesis uses imaging flow cytometry to examine the ability of human NK cells to interact with erythrocytes parasitised with the human malaria parasite Plasmodium falciparum (PRBCs). Although several limitations of this technology became apparent, I was able to establish that conjugates between NK cells and PRBCs form within 30 minutes of co-incubation and persist for up to 3 hours. PRBCs were observed forming conjugates with both CD56bright and CD56dimCD57+ NK cells. The role of antibody in promoting NK cell responses via CD16 was then assessed in two models. Firstly, an in vitro model using NK cells and plasma from individuals vaccinated with trivalent influenza vaccine was used to establish assay conditions and to investigate the mechanisms by which CD16 is downregulated after antibody-dependent activation. In this model, I have shown that influenza antigen-antibody complexes are able to induce downregulation of CD16 on NK cells, resulting in degranulation. These antibody dependent functions are more potent in highly differentiated CD56dimCD57+ NK cells. Using imaging flow cytometry, I have also shown that downregulation of CD16 after ligation is due to shedding of the molecule from the surface of the NK cell, rather than through a process of internalisation. Secondly, I established an in vitro system to investigate the impact of antibody on NK cell responses to PRBCs in Gambian and UK resident individuals. This study also assessed the contributions of different NK cell differentiation subsets to these responses. I have shown that NK cells are able to mount a robust antibody-dependent response to PRBCs, involving production of IFN-γ and degranulation. I have also shown that NK cells vary in their responsiveness to antibody stimulation, with 'adaptive' FcεRIγ- and 'differentiated' CD57+ NK cells demonstrating enhanced responses to anti-malarial antibodies. Finally, I have shown that the cytokines interleukin 12 and interleukin 18 contribute to the anti-malarial antibody-dependent response in certain NK cell subsets, as does ligation of CD2 on the NK cell.
Supervisor: Riley, E. M. ; Goodier, M. R. Sponsor: Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral