Abstract
NK cells have been shown to display adaptive traits such as memory formation akin to T and B lymphocytes. Here we show that Zika virus infection induces memory like NK cells that express CD27. Strikingly, these cells exhibit stem-like features that include expansion capacity, self-renewal pathway, differentiation into effector cells, longer telomeres and gene signature associated with hematopoietic stem cell (HSC) progenitors. This subset shared transcriptional and epigenetic changes with memory CD8 T cells, stem cells and stem like T cells. These NK cells with memory and stem cell features, which we term “NK memory stem cells”, demonstrated greater antiviral potential than CD27- or naïve CD27+ NK when adoptively transferred to Zika infected mice. Our results also suggest a role for the transcription factor TCF-1 in memory and stemness features of this NK subset. This study defines a unique TCF1hi CD27+ NK subset with memory capacity and stem cell features that play a role in antiviral immunity.
Highlights
Natural killer (NK) cells play roles in clearance of virus infected cells and tumor surveillance and in the production of cytokines that orchestrate adaptive immune responses
The CD8 T cells exhibiting stem cell like properties occur in chronic viral infection and tumors and those stem like T cells respond to PD-1 blockade undergoing proliferative burst resulting in viral clearance and tumor immunity
It is unclear whether innate immune cells such as NK cells contain a subset with stem cell features and memory capacity
Summary
Natural killer (NK) cells play roles in clearance of virus infected cells and tumor surveillance and in the production of cytokines that orchestrate adaptive immune responses. NK cells are considered part of the innate defense mechanism but several recent reports indicate that NK cells can express immune memory responding more effectively to secondary stimulation just like cells of the adaptive immune system [4,5,6,7]. The immunological memory phenotype of NK cells involves robust secondary expansion to haptens, cytokines or microbes. Murine NK cells possessing an activating receptor, Ly49H, undergo robust expansion, contraction, and memory formation after mouse cytomegalovirus (MCMV) infection [5]. Following infection with MCMV lacking m157, memory NK cell responses were absent. Memory NK cells provided more effective protection against MCMV or responded better to haptens than did naïve NK cells [5,7]
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