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LIR1 expressing human Natural Killer cell subsets differentially recognize isolates of human cytomegalovirus through the viral MHC Class I homolog UL18

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Chen, Kevin C 
Stanton, Richard J 
Banat, Jareer J 
Wills, Mark R 


Immune responses of Natural Killer (NK) cell are controlled by the balance between activating and inhibitory receptors, but the expression of these receptors varies between cells within an individual. Although NK cells are a component of the innate immune system, particular NK cell subsets expressing Ly49H are positively selected and increase in frequency in response to cytomegalovirus infection in mice. Recent evidence suggests that in humans certain NK subsets also have an increased frequency in the blood of HCMV infected individuals. However whether these subsets differ in their capacity of direct control of HCMV infected cells remains unclear. In this study we developed a novel in vitro assay to assess whether human NK cells subsets have differential abilities to inhibit HCMV growth and dissemination. NK cells expressing or lacking NKG2C did not display any differences when controlling viral dissemination. However, when in vitro expanded NK cells were used, cells expressing or lacking the inhibitory receptor Leukocyte Immunoglobulin-like receptor 1 (LIR1) were differentially able to control dissemination. Surprisingly, the ability of LIR1+ NK cells to control virus spread differed between HCMV viral strains, and this phenomenon was dependent on amino acid sequences within the viral ligand UL18. Together, the results here outlined an in vitro technique to compare the long-term immune responses of different human NK cell subsets, and suggest, for the first time, phenotypically defined human NK cell subsets may differentially recognise HCMV infected.

IMPORTANCE HCMV infection is ubiquitous in most populations, it is not cleared by the host after primary infection but persists for life. The innate and adaptive immune system controls the spread of virus, of which Natural Killer (NK) cells play a pivotal role. NK cells can respond to HCMV infection by rapid, short-term non-specific innate responses, but evidence from murine studies suggested NK cells may display a long-term, memory like responses to murine cytomegalovirus infection. In this study, we developed a new assay that examines human NK cell subsets that have been suggested to play a long-term memory-like response to HCMV infection. We show that changes in a HCMV viral protein that interacts with an NK cell receptor can change the ability of NK cell subsets to control HCMV while the acquisition odf another receptor has no effect on virus control.


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Journal of Virology

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American Society for Microbiology
This work was funded by the Wellcome Trust Grant WT094107AIA, the UK Medical Research Council Grant G0701279, MR/L008734/1 and MR/K021087/1 and supported by the NIHR Cambridge BRC Cell Phenotyping hub. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.