Natural killer cell responses to Plasmodium falciparum-infected red blood cells.

NK cells are known to respond in vitro to P. falciparum-infected red blood cells (iRBCs), although responses are highly heterogeneous between donors. Although their role during malaria infection is not fully understood, they may play a role in cytokine production during early infection, and furthermore may interact with and kill iRBCs. The work described in this thesis examines the role of NK cell receptors in determining the functional outcomes of NK cell activation by iRBCs, focusing on NK cell responses to exogenous cytokines and the phenotypic and functional profiles of NK cells from malaria naive (LSHTM) and malaria exposed (Ugandan) subjects. In a model of early activation of NK cells by accessory cell-derived cytokines, I have shown a key role for IL-18 in mediating NK cell responses during both primary and secondary immune responses as IL-18 synergises with cytokines from the common gamma chain family. NK cells from LSHTM donors showed low background expression of IFN- and CD25, but responded to iRBCs by secretion of IFN-, which was potentiated by exogenous IL-15. By contrast, NK cells from Ugandan donors showed higher background CD25 expression and signs of in vivo/ex vivo preactivation and enhanced responsiveness to IL-15, but did not make any appreciable response to iRBCs. Potential explanations for these findings are explored and discussed. KIR genotype and KIR expression also varied between LSHTM and Ugandan donors. Specifically, expansions of KIR2DL1+ CD57+ NKG2C+ NK cell populations (possibly driven by human cytomegalovirus (HCMV) infection) were observed in the Ugandan donors. Conversely, percentages of KIR2DL3+ and 2DS4+ NK cells were higher among LSHTM donors, indicating that HLA genotype or allelic KIR polymorphisms may influence KIR expression. Finally, the formation of NK-iRBC conjugates, which may be a precursor to NK cellmediated killing of iRBCs, was observed in cells from nearly all donors, but did not correlate with other functional responses. Analysis of KIR expression and NK cell functional responses indicated that donors expressing inhibitory KIR2DL5 had reduced numbers of conjugates. Further experiments indicated that KIR2DL5 might be specifically upregulated after incubation with iRBCs, and that individuals carrying a normally non-expressed KIR2DL5 gene may be able to express this gene under certain circumstances. This tentatively suggests a role for KIR2DL5 during NK cell responses to malaria infection, and suggests a possible function for a common but frequently non-expressed gene. In summary, my work suggests that NK cell responses are strongly influenced by cytokine receptor and KIR expression, which in turn depend on NK cell maturation status. KIR expression patterns may in part explain differential NK responses to iRBCs between LSHTM and Ugandan donors. I also propose a possible role for KIR2DL5 in malaria infection, and a reason for the low expression of this gene in African populations.