Memory Like Nk Cells Display Stem Cell Like Properties After Zika Virus Infection

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 naive 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 TCF1(hi) CD27(+) NK subset with memory capacity and stem cell features that play a role in antiviral immunity.Author summaryThe 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. In the present study, using a mouse model of Zika virus infection, we identify memory like NK responses to Zika virus. The detailed transcriptomics, chromatin accessibility analysis and functional studies showed that these memory like NK cells also presented stem cell-like properties and shared signatures with memory CD8 T cells, stem cells and stem like T cells from chronic infection and tumors. These cells also demonstrated greater antiviral potential than naive CD27(+) NK cells when adoptively transferred to Zika infected mice. Our work highlights stem cell memory features in NK cells that are beneficial in fighting viral infection.