NK cell response to virus infection is compromised in the absence of type I interferons (IFNs). Memory like NK response to ZIKV infection Moreover, unlike terminally exhausted CD8 T cells, transcriptomics and epigenetic landscape of NK SCM cells indicate that these cells appear resistant to developing functional exhaustion. In this report we fully characterize what we refer to as “NK memory stem cells” (NK SCM) and show that such cells can act effectively to control Zika virus (ZIKV) infection in a mouse model system. Indeed, memory like NK cells share some properties with progenitor exhausted memory CD8 cells (aka stem like CD8 T cells) found in chronic viral infections and some cancers. The subset of NK cell that exerts memory may express some properties shared with memory CD8 T cells and as we show in this report several properties which are also characteristic of self-renewing hemopoietic stem cells (HSC). Whether innate immune cells such as NK cells include a similar stem cell memory subset and contribute to anti-microbial defense is not known. Such subsets also occur in chronic viral infections as well as in tumors and were found to undergo a proliferative burst after PD-1 blockade therapy. These stemness properties include long term quiescence, self-renewal and multipotent ability to generate memory as well as terminal effector cells. The CD8 T cell compartment harbors a subset that exhibits memory and stem cell properties. Memory NK cells provided more effective protection against MCMV or responded better to haptens than did naïve NK cells. Following infection with MCMV lacking m157, memory NK cell responses were absent. Ly49H+ NK cells recognize infected cells expressing the MCMV-encoded protein, m157. Murine NK cells possessing an activating receptor, Ly49H, undergo robust expansion, contraction, and memory formation after mouse cytomegalovirus (MCMV) infection. The immunological memory phenotype of NK cells involves robust secondary expansion to haptens, cytokines or microbes. Traditionally NK cells are considered part of the innate defense mechanism but several recent reports indicate that NK cells can also express immune memory responding more effectively to secondary stimulation just like cells of the adaptive immune system. Humans lacking NK cells suffer from life-threatening herpes virus infections and are more susceptible to some cancers thus highlighting the importance of NK cells. 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 funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. and Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Texas, USA. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are in the manuscript, the supplemental files and the RNA-seq and ATAC-seq data of NK cells described in this publication have been deposited in NCBI’s Gene Expression Omnibus and can be accessed at the following accession numbers: GSE148205 and GSE148780.įunding: This work was supported by University of Texas STARS award to S.M. Received: JAccepted: NovemPublished: December 28, 2020Ĭopyright: © 2020 Kujur et al. PLoS Pathog 16(12):Įditor: Simona Stäger, INRS - Institut Armand Frappier, CANADA This study defines a unique TCF1 hi CD27 + NK subset with memory capacity and stem cell features that play a role in antiviral immunity.Ĭitation: Kujur W, Murillo O, Adduri RSR, Vankayalapati R, Konduru NV, Mulik S (2020) Memory like NK cells display stem cell like properties after Zika virus infection.
Our results also suggest a role for the transcription factor TCF-1 in memory and stemness features of this NK subset.
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. This subset shared transcriptional and epigenetic changes with memory CD8 T cells, stem cells and stem like T cells. 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.
Here we show that Zika virus infection induces memory like NK cells that express CD27. NK cells have been shown to display adaptive traits such as memory formation akin to T and B lymphocytes.
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