Giuseppe
Emeritus
[Source: PLoS ONE, full page: (LINK). Abstract, edited.]
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Research Article
Activation Mechanisms of Natural Killer Cells during Influenza Virus Infection
Ilwoong Hwang, Jeannine M. Scott, Tejaswi Kakarla, David M. Duriancik, Seohyun Choi, Chunghwan Cho, Taehyung Lee, Hyojin Park, Anthony R. French, Eleni Beli, Elizabeth Gardner, Sungjin Kim
Affiliation: [See the original page.]
Abstract
During early viral infection, activation of natural killer (NK) cells elicits the effector functions of target cell lysis and cytokine production. However, the cellular and molecular mechanisms leading to NK cell activation during viral infections are incompletely understood. In this study, using a model of acute viral infection, we investigated the mechanisms controlling cytotoxic activity and cytokine production in response to influenza (flu) virus. Analysis of cytokine receptor deficient mice demonstrated that type I interferons (IFNs), but not IL-12 or IL-18, were critical for the NK cell expression of both IFN-γ and granzyme B in response to flu infection. Further, adoptive transfer experiments revealed that NK cell activation was mediated by type I IFNs acting directly on NK cells. Analysis of signal transduction molecules showed that during flu infection, STAT1 activation in NK cells was completely dependent on direct type I IFN signaling, whereas STAT4 activation was only partially dependent. In addition, granzyme B induction in NK cells was mediated by signaling primarily through STAT1, but not STAT4, while IFN-γ production was mediated by signaling through STAT4, but not STAT1. Therefore, our findings demonstrate the importance of direct action of type I IFNs on NK cells to mount effective NK cell responses in the context of flu infection and delineate NK cell signaling pathways responsible for controlling cytotoxic activity and cytokine production.
Citation: Hwang I, Scott JM, Kakarla T, Duriancik DM, Choi S, et al. (2012) Activation Mechanisms of Natural Killer Cells during Influenza Virus Infection. PLoS ONE 7(12): e51858. doi:10.1371/journal.pone.0051858
Editor: Ali A. Ashkar, McMaster University, Canada
Received: August 6, 2012; Accepted: November 13, 2012; Published: December 31, 2012
Copyright: ? 2012 Hwang et al. 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.
Funding: This work was supported by National Institute on Aging, 5R01AG034949 to EG and National Agenda Project grant from the Korea Research Council of Fundamental Science & Technology in Republic of Korea to SK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: kimsj@msu.edu
-Activation Mechanisms of Natural Killer Cells during Influenza Virus Infection
Ilwoong Hwang, Jeannine M. Scott, Tejaswi Kakarla, David M. Duriancik, Seohyun Choi, Chunghwan Cho, Taehyung Lee, Hyojin Park, Anthony R. French, Eleni Beli, Elizabeth Gardner, Sungjin Kim
Affiliation: [See the original page.]
Abstract
During early viral infection, activation of natural killer (NK) cells elicits the effector functions of target cell lysis and cytokine production. However, the cellular and molecular mechanisms leading to NK cell activation during viral infections are incompletely understood. In this study, using a model of acute viral infection, we investigated the mechanisms controlling cytotoxic activity and cytokine production in response to influenza (flu) virus. Analysis of cytokine receptor deficient mice demonstrated that type I interferons (IFNs), but not IL-12 or IL-18, were critical for the NK cell expression of both IFN-γ and granzyme B in response to flu infection. Further, adoptive transfer experiments revealed that NK cell activation was mediated by type I IFNs acting directly on NK cells. Analysis of signal transduction molecules showed that during flu infection, STAT1 activation in NK cells was completely dependent on direct type I IFN signaling, whereas STAT4 activation was only partially dependent. In addition, granzyme B induction in NK cells was mediated by signaling primarily through STAT1, but not STAT4, while IFN-γ production was mediated by signaling through STAT4, but not STAT1. Therefore, our findings demonstrate the importance of direct action of type I IFNs on NK cells to mount effective NK cell responses in the context of flu infection and delineate NK cell signaling pathways responsible for controlling cytotoxic activity and cytokine production.
Citation: Hwang I, Scott JM, Kakarla T, Duriancik DM, Choi S, et al. (2012) Activation Mechanisms of Natural Killer Cells during Influenza Virus Infection. PLoS ONE 7(12): e51858. doi:10.1371/journal.pone.0051858
Editor: Ali A. Ashkar, McMaster University, Canada
Received: August 6, 2012; Accepted: November 13, 2012; Published: December 31, 2012
Copyright: ? 2012 Hwang et al. 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.
Funding: This work was supported by National Institute on Aging, 5R01AG034949 to EG and National Agenda Project grant from the Korea Research Council of Fundamental Science & Technology in Republic of Korea to SK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: kimsj@msu.edu
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