Respiratory Influenza Virus Infection Induces Memory-Like Liver NK Cells
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Respiratory Influenza Virus Infection Induces Memory-like Liver NK Cells in Mice Tingting Li, Jian Wang, Yanshi Wang, Yongyan Chen, Haiming Wei, Rui Sun and Zhigang Tian This information is current as of September 25, 2021. J Immunol published online 28 December 2016 http://www.jimmunol.org/content/early/2016/12/21/jimmun ol.1502186 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/12/21/jimmunol.150218 Material 6.DCSupplemental Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 25, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published December 28, 2016, doi:10.4049/jimmunol.1502186 The Journal of Immunology Respiratory Influenza Virus Infection Induces Memory-like Liver NK Cells in Mice Tingting Li,* Jian Wang,* Yanshi Wang,* Yongyan Chen,* Haiming Wei,* Rui Sun,*,† and Zhigang Tian*,† Although NK cells are classified as innate immune cells, recent studies have demonstrated the transformation of NK cells into long-lived memory cells that contribute to secondary immune responses in certain mouse models. However, whether NK cells mount an Ag- specific memory response to acute influenza virus infection has not yet been examined. Here, we show that, consistent with previous studies, lung NK cells play an important role in controlling viral proliferation after primary influenza virus infection. However, al- though lung NK cells display a memory phenotype at the late stage of infection, these cells do not protect mice against secondary influenza virus infection. Interestingly, liver NK cells from influenza virus–infected mice possess a memory phenotype and protect 2 mice against secondary influenza virus infection. Memory-like liver NK cells display a CD49a+DX5 phenotype, and the adoptive Downloaded from transfer of purified liver CD49a+DX52 NK cells into naive mice followed by viral infection results in protective immunity and decreased viral titer. Moreover, we demonstrate that primary inactivated influenza virus induces memory NK cells residing in the liver of Rag12/2 mice. Collectively, these data suggest that liver CD49a+DX52 NK cells remember encountered Ag from influenza virus after primary infection and are more protective upon subsequent infection. The Journal of Immunology, 2017, 198: 000–000. mmune memory is a feature of the adaptive immune system. memory NK cells provide effective and specific protection against http://www.jimmunol.org/ However, recent studies have demonstrated that NK cells, these viruses. However, the sensitization of NK cells to influenza A I important components of the innate immune system, also virus does not require NKp46-hemagglutinin (-HA) interactions. mediate Ag-specific recall responses, similar to Tand B cells (1–4). With respect to cytokine-induced memory-like NK cells, Cooper Three major viewpoints of NK cell memory initially arose from et al. have shown that the response to restimulation ex vivo either the studies of NK cell memory to recall to skin contact hyper- with cytokines or through their activating receptors Ly49H or sensitive chemical hapten and noninfectious virus-like particles (1, NK1.1, indicates IFN-g production is more robust than resting NK 2), cytokines (3), and mouse CMV (MCMV) (4). In chemical cells (2, 3). This enhanced response could be detected even 3 wk hapten-induced contact hypersensitivity (CHS) mouse models, after transfer into naive hosts. Using an MCMV infection mouse by guest on September 25, 2021 RAG-deficient mice lacking T and B cells exhibit CHS responses model, Sun et al. (4) demonstrated that NK cells bearing the Ly49H elicited through hapten exposure, and hapten-specific memory- receptor specifically recognize MCMV-infected cells expressing like NK cells typically reside in the liver and display a CD49a+ 2 the viral glycoprotein m157 and eventually form MCMV-specific DX5 phenotype (1, 2, 5). Using noninfectious virus-like parti- immune memory. Together, these studies demonstrate the existence cles, Silke Paust and colleagues showed that liver NK cells re- of NK cell memory. Moreover, memory NK cells mediate an ef- member influenza virus, vesicular stomatitis virus, and HIV, and fective protection against vaccinia virus (6) and HSV-2 (7) in the absence of T and B cells. More recently, robust, durable, Ag-specific NK cell memory can be induced in primates after both SIV (8) *The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic infection and Ad26 vector vaccination. Therefore, there is mounting Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; and †Collaborative Innovation evidence for memory NK cell memory response in different models Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for of viral disease in both mice and primates (9, 10). As more pathogen Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China components recognized by NK cell receptors, including activating ORCIDs: 0000-0003-2754-9784 (T.L.); 0000-0002-4127-322X (J.W.). and inhibitory receptors, are characterized (11, 12), additional in- fectious disease models, especially natural pathogen infection Received for publication October 8, 2016. Accepted for publication November 22, 2016. mouse models, will be required to further analyze the mechanisms This work was supported by Ministry of Science and Technology of China 973 Basic underlying NK cell memory formation during infection. Science Project Grants 2013CB944902 and 2013CB530506 and National Natural Influenza virus infection is a common respiratory disease. The Science Foundation of China Grants 81361120388, 31400783, 91542114, first line of defense against influenza virus infection is mediated 31300727, and 31300753. by the innate immune system, which controls the initial response to Address correspondence and reprint requests to Dr. Zhigang Tian, Dr. Rui Sun, and Dr. Jian Wang, School of Life Sciences and Medical Center, University of Science viral infection and regulation of the adaptive immune response (13, and Technology of China, 443 Huangshan Road, Hefei, Anhui 230027, China. E-mail 14). As an important part of the innate immune system, NK cells addresses: [email protected] (Z.T.), [email protected] (R.S.), and [email protected]. edu.cn (J.W.) have a higher frequency in the lungs than in any of the other The online version of this article contains supplemental material. tissues (15, 16). Most of the data from animal models suggest that NK cells may be directly antiviral, and able to recognize and kill Abbreviations used in this article: AsGM1, asialo-GM1; CHS, contact hypersensi- tivity; HA, hemagglutinin; Hopx, homeobox-only protein; i.n, intranasal(ly); MCMV, virus-infected cells through interactions with influenza hemag- mouse CMV; MDCK, Madin-Darby canine kidney; PR8, mouse-adapted influenza A/ glutinin and the receptor, NKp46 (17–19). However, NK cells can PR/8/34 strain; RSV, respiratory syncytial virus; WT, wild-type. also contribute to pathological damage of host tissues with high Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 dose influenza infection (20, 21). These studies raise the interesting www.jimmunol.org/cgi/doi/10.4049/jimmunol.1502186 2 INFLUENZA INFECTION INDUCES INNATE IMMUNE MEMORY possibility that NK cells may play dual roles during influenza in- i.n. with influenza virus. The immunized mice were i.v. administered anti- fection, conferring protection or inducing pathology, depending NK1.1 (PK136) or PBS 1 d prior to infection. on the viral dose. Whether memory NK cells can provide protection Determination of viral loads against subsequent influenza infection and the related immune mechanisms is poorly understood. Thus, a live influenza virus The viral loads in the lungs were determined through quantitative real-time infection mouse model might provide an adequate platform to PCR analysis at the indicated times after PR8 infection. Briefly, total RNA was extracted from whole lung tissue, and cDNA was subsequently syn- study the immune memory of NK cells. thesized. The viral loads in each sample were calculated through relative In the current study, to determine whether NK cells could mount quantification, and the ratio of viral RNA to b-actin mRNA 1 d after PR8 an Ag-specific memory response to acute respiratory influenza infection in wild-type (WT) mice was used as a control. The following virus infection, we first explored the existence of memory-like NK primers were specific for the matrix protein of influenza virus (23): 59- GGACTGCAGCGTAGACGCTT-39 (forward) and 59-CATCCTGTTGTA- cells after viral infection and subsequently characterized the TATGAGGCCCAT-39