{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T19:27:38Z","timestamp":1793647658018,"version":"4.5.1"},"reference-count":55,"publisher":"Rockefeller University Press","issue":"4","license":[{"start":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T00:00:00Z","timestamp":1581379200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2020,10,5]],"date-time":"2020-10-05T00:00:00Z","timestamp":1601856000000},"content-version":"vor","delay-in-days":237,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,4,6]]},"abstract":"<jats:p>Natural killer (NK) cells are innate lymphocytes that exhibit adaptive features, such as clonal expansion and memory, during viral infection. Although activating receptor engagement and proinflammatory cytokines are required to drive NK cell clonal expansion, additional stimulatory signals controlling their proliferation remain to be discovered. Here, we describe one such signal that is provided by the adrenergic nervous system, and demonstrate that cell-intrinsic adrenergic signaling is required for optimal adaptive NK cell responses. Early during mouse cytomegalovirus (MCMV) infection, NK cells up-regulated Adrb2 (which encodes the \u03b22-adrenergic receptor), a process dependent on IL-12 and STAT4 signaling. NK cell\u2013specific deletion of Adrb2 resulted in impaired NK cell expansion and memory during MCMV challenge, in part due to a diminished proliferative capacity. As a result, NK cell-intrinsic adrenergic signaling was required for protection against MCMV. Taken together, we propose a novel role for the adrenergic nervous system in regulating circulating lymphocyte responses to viral infection.<\/jats:p>","DOI":"10.1084\/jem.20190549","type":"journal-article","created":{"date-parts":[[2020,1,14]],"date-time":"2020-01-14T02:21:29Z","timestamp":1578968489000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":61,"title":["Cell-intrinsic adrenergic signaling controls the adaptive NK cell response to viral infection"],"prefix":"10.1084","volume":"217","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9735-2253","authenticated-orcid":true,"given":"Carlos","family":"Diaz-Salazar","sequence":"first","affiliation":[{"name":"Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 1"},{"name":"Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina","family":"Bou-Puerto","sequence":"additional","affiliation":[{"name":"Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 1"},{"name":"Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana M.","family":"Mujal","sequence":"additional","affiliation":[{"name":"Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen M.","family":"Lau","sequence":"additional","affiliation":[{"name":"Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8037-0076","authenticated-orcid":true,"given":"Madlaina","family":"von Hoesslin","sequence":"additional","affiliation":[{"name":"Division of Animal Physiology and Immunology, Technical University of Munich, Freising, Germany 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietmar","family":"Zehn","sequence":"additional","affiliation":[{"name":"Division of Animal Physiology and Immunology, Technical University of Munich, Freising, Germany 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8062-9033","authenticated-orcid":true,"given":"Joseph C.","family":"Sun","sequence":"additional","affiliation":[{"name":"Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 1"},{"name":"Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 2"},{"name":"Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 4"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2020,2,11]]},"reference":[{"key":"2026041423510697500_bib1","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1016\/j.immuni.2018.04.018","article-title":"Transcription Factor IRF8 Orchestrates the Adaptive Natural Killer Cell Response","volume":"48","author":"Adams","year":"2018","journal-title":"Immunity."},{"key":"2026041423510697500_bib2","doi-asserted-by":"publisher","first-page":"1796","DOI":"10.4049\/jimmunol.166.3.1796","article-title":"NK1.1+ cells and murine cytomegalovirus infection: what happens in situ?","volume":"166","author":"Andrews","year":"2001","journal-title":"J. Immunol."},{"key":"2026041423510697500_bib3","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1126\/science.1070884","article-title":"Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors","volume":"296","author":"Arase","year":"2002","journal-title":"Science."},{"key":"2026041423510697500_bib4","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1038\/ni.2876","article-title":"The transcription factor Zbtb32 controls the proliferative burst of virus-specific natural killer cells responding to infection","volume":"15","author":"Beaulieu","year":"2014","journal-title":"Nat. Immunol."},{"key":"2026041423510697500_bib5","doi-asserted-by":"publisher","first-page":"6768","DOI":"10.4049\/jimmunol.180.10.6768","article-title":"Ly49H+ NK cells migrate to and protect splenic white pulp stroma from murine cytomegalovirus infection","volume":"180","author":"Bekiaris","year":"2008","journal-title":"J. Immunol."},{"key":"2026041423510697500_bib6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0145635","article-title":"Stress-Induced In Vivo Recruitment of Human Cytotoxic Natural Killer Cells Favors Subsets with Distinct Receptor Profiles and Associates with Increased Epinephrine Levels","volume":"10","author":"Bigler","year":"2015","journal-title":"PLoS One."},{"key":"2026041423510697500_bib7","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.bbi.2015.10.008","article-title":"Acute psychological stress induces short-term variable immune response","volume":"53","author":"Breen","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"2026041423510697500_bib8","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/nature23469","article-title":"Neuronal regulation of type 2 innate lymphoid cells via neuromedin U","volume":"549","author":"Cardoso","year":"2017","journal-title":"Nature."},{"key":"2026041423510697500_bib9","doi-asserted-by":"publisher","first-page":"16694","DOI":"10.1074\/jbc.274.24.16694","article-title":"Targeted disruption of the beta2 adrenergic receptor gene","volume":"274","author":"Chruscinski","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2026041423510697500_bib10","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1084\/jem.194.1.29","article-title":"Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H","volume":"194","author":"Daniels","year":"2001","journal-title":"J. Exp. Med."},{"key":"2026041423510697500_bib11","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1038\/ni714","article-title":"Specific and nonspecific NK cell activation during virus infection","volume":"2","author":"Dokun","year":"2001","journal-title":"Nat. Immunol."},{"key":"2026041423510697500_bib12","doi-asserted-by":"publisher","first-page":"6394","DOI":"10.4049\/jimmunol.181.9.6394","article-title":"Ly49h-deficient C57BL\/6 mice: a new mouse cytomegalovirus-susceptible model remains resistant to unrelated pathogens controlled by the NK gene complex","volume":"181","author":"Fodil-Cornu","year":"2008","journal-title":"J. Immunol."},{"key":"2026041423510697500_bib13","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.cell.2015.12.023","article-title":"Neuro-immune Interactions Drive Tissue Programming in Intestinal Macrophages","volume":"164","author":"Gabanyi","year":"2016","journal-title":"Cell."},{"key":"2026041423510697500_bib14","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1038\/ni1322","article-title":"Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1","volume":"7","author":"Gazit","year":"2006","journal-title":"Nat. Immunol."},{"key":"2026041423510697500_bib15","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.smim.2017.08.012","article-title":"Memory responses of natural killer cells","volume":"31","author":"Geary","year":"2017","journal-title":"Semin. Immunol."},{"key":"2026041423510697500_bib16","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1016\/j.celrep.2018.07.060","article-title":"Non-redundant ISGF3 Components Promote NK Cell Survival in an Auto-regulatory Manner during Viral Infection","volume":"24","author":"Geary","year":"2018","journal-title":"Cell Reports."},{"key":"2026041423510697500_bib17","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1146\/annurev-immunol-042718-041812","article-title":"Neuro-Immune Cell Units: A New Paradigm in Physiology","volume":"37","author":"Godinho-Silva","year":"2019","journal-title":"Annu. Rev. Immunol."},{"key":"2026041423510697500_bib18","doi-asserted-by":"publisher","first-page":"2076","DOI":"10.1002\/eji.200838550","article-title":"Intrasplenic trafficking of natural killer cells is redirected by chemokines upon inflammation","volume":"38","author":"Gr\u00e9goire","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"2026041423510697500_bib19","doi-asserted-by":"publisher","first-page":"3664","DOI":"10.1182\/blood-2004-05-2058","article-title":"Imprint of human cytomegalovirus infection on the NK cell receptor repertoire","volume":"104","author":"Gum\u00e1","year":"2004","journal-title":"Blood."},{"key":"2026041423510697500_bib20","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1083\/jcb.200809113","article-title":"The sympathetic tone mediates leptin\u2019s inhibition of insulin secretion by modulating osteocalcin bioactivity","volume":"183","author":"Hinoi","year":"2008","journal-title":"J. Cell Biol."},{"key":"2026041423510697500_bib21","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1097\/WNR.0000000000000036","article-title":"The effect of the sympathetic nervous system on splenic natural killer cell activity in mice administered the Lactobacillus pentosus strain S-PT84","volume":"24","author":"Izumo","year":"2013","journal-title":"Neuroreport."},{"key":"2026041423510697500_bib22","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1038\/382174a0","article-title":"Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice","volume":"382","author":"Kaplan","year":"1996","journal-title":"Nature."},{"key":"2026041423510697500_bib23","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.coi.2018.11.002","article-title":"Neuronal regulation of innate lymphoid cells","volume":"56","author":"Klose","year":"2019","journal-title":"Curr. Opin. Immunol."},{"key":"2026041423510697500_bib24","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1038\/nature23676","article-title":"The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation","volume":"549","author":"Klose","year":"2017","journal-title":"Nature."},{"key":"2026041423510697500_bib25","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/ni1581","article-title":"Up on the tightrope: natural killer cell activation and inhibition","volume":"9","author":"Lanier","year":"2008","journal-title":"Nat. Immunol."},{"key":"2026041423510697500_bib26","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.coi.2018.05.013","article-title":"The widening spectrum of immunological memory","volume":"54","author":"Lau","year":"2018","journal-title":"Curr. Opin. Immunol."},{"key":"2026041423510697500_bib27","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1038\/s41590-018-0176-1","article-title":"Epigenetic control of innate and adaptive immune memory","volume":"19","author":"Lau","year":"2018","journal-title":"Nat. Immunol."},{"key":"2026041423510697500_bib28","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1016\/j.immuni.2017.02.015","article-title":"Brain Ischemia Suppresses Immunity in the Periphery and Brain via Different Neurogenic Innervations","volume":"46","author":"Liu","year":"2017","journal-title":"Immunity."},{"key":"2026041423510697500_bib29","first-page":"83","article-title":"L\u2019action de l\u2019adr\u00e9naline sur la sang","volume":"16","author":"L\u0153per","year":"1904","journal-title":"Arch. Med. Exp. Anat. Pathol."},{"key":"2026041423510697500_bib30","doi-asserted-by":"publisher","first-page":"14725","DOI":"10.1073\/pnas.1110900108","article-title":"Expansion of a unique CD57+NKG2Chi natural killer cell subset during acute human cytomegalovirus infection","volume":"108","author":"Lopez-Verg\u00e8s","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2026041423510697500_bib31","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.4049\/jimmunol.1402001","article-title":"Cutting edge: stage-specific requirement of IL-18 for antiviral NK cell expansion","volume":"194","author":"Madera","year":"2015","journal-title":"J. Immunol."},{"key":"2026041423510697500_bib32","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1084\/jem.20150712","article-title":"Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide","volume":"213","author":"Madera","year":"2016","journal-title":"J. Exp. Med."},{"key":"2026041423510697500_bib33","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/S0092-8674(00)81288-X","article-title":"Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway","volume":"84","author":"Meraz","year":"1996","journal-title":"Cell."},{"key":"2026041423510697500_bib34","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1126\/science.aan4829","article-title":"\u03b22-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses","volume":"359","author":"Moriyama","year":"2018","journal-title":"Science."},{"key":"2026041423510697500_bib35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0182416","article-title":"Neuroanatomy of the spleen: Mapping the relationship between sympathetic neurons and lymphocytes","volume":"12","author":"Murray","year":"2017","journal-title":"PLoS One."},{"key":"2026041423510697500_bib36","doi-asserted-by":"publisher","first-page":"18324","DOI":"10.1073\/pnas.1112064108","article-title":"Fate mapping analysis of lymphoid cells expressing the NKp46 cell surface receptor","volume":"108","author":"Narni-Mancinelli","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2026041423510697500_bib37","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1016\/j.immuni.2015.09.013","article-title":"Natural Killer Cell Memory","volume":"43","author":"O\u2019Sullivan","year":"2015","journal-title":"Immunity."},{"key":"2026041423510697500_bib38","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1016\/j.cmet.2016.01.011","article-title":"Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution","volume":"23","author":"Pedersen","year":"2016","journal-title":"Cell Metab."},{"key":"2026041423510697500_bib39","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1084\/jem.20021098","article-title":"Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation","volume":"198","author":"Prass","year":"2003","journal-title":"J. Exp. Med."},{"key":"2026041423510697500_bib40","doi-asserted-by":"publisher","first-page":"3531","DOI":"10.1084\/jem.20171048","article-title":"Host resistance to endotoxic shock requires the neuroendocrine regulation of group 1 innate lymphoid cells","volume":"214","author":"Quatrini","year":"2017","journal-title":"J. Exp. Med."},{"key":"2026041423510697500_bib41","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1111\/imr.12707","article-title":"Neuroendocrine regulation of innate lymphoid cells","volume":"286","author":"Quatrini","year":"2018","journal-title":"Immunol. Rev."},{"key":"2026041423510697500_bib42","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1038\/s41590-018-0185-0","article-title":"Endogenous glucocorticoids control host resistance to viral infection through the tissue-specific regulation of PD-1 expression on NK cells","volume":"19","author":"Quatrini","year":"2018","journal-title":"Nat. Immunol."},{"key":"2026041423510697500_bib43","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aan3796","article-title":"Core-binding factor \u03b2 and Runx transcription factors promote adaptive natural killer cell responses","volume":"2","author":"Rapp","year":"2017","journal-title":"Sci. Immunol."},{"key":"2026041423510697500_bib44","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1038\/ni.3227","article-title":"Antigen-specific NK cell memory in rhesus macaques","volume":"16","author":"Reeves","year":"2015","journal-title":"Nat. Immunol."},{"key":"2026041423510697500_bib45","doi-asserted-by":"publisher","first-page":"11008","DOI":"10.1073\/pnas.0803237105","article-title":"Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia","volume":"105","author":"Rosas-Ballina","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2026041423510697500_bib46","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1038\/nature01080","article-title":"Active genes are tri-methylated at K4 of histone H3","volume":"419","author":"Santos-Rosa","year":"2002","journal-title":"Nature."},{"key":"2026041423510697500_bib47","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1038\/s41586-018-0774-y","article-title":"Disruption of a\u00a0self-amplifying catecholamine loop reduces cytokine release syndrome","volume":"564","author":"Staedtke","year":"2018","journal-title":"Nature."},{"key":"2026041423510697500_bib48","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1038\/nri3044","article-title":"NK cell development, homeostasis and function: parallels with CD8+ T cells","volume":"11","author":"Sun","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"2026041423510697500_bib49","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/nature07665","article-title":"Adaptive immune features of natural killer cells","volume":"457","author":"Sun","year":"2009","journal-title":"Nature."},{"key":"2026041423510697500_bib50","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1084\/jem.20111760","article-title":"Proinflammatory cytokine signaling required for the generation of natural killer cell memory","volume":"209","author":"Sun","year":"2012","journal-title":"J. Exp. Med."},{"key":"2026041423510697500_bib51","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1016\/j.bbi.2012.07.002","article-title":"\u03b2-Adrenergic receptor mediated increases in activation and function of natural killer cells following repeated social disruption","volume":"26","author":"Tarr","year":"2012","journal-title":"Brain Behav. Immun."},{"key":"2026041423510697500_bib52","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1126\/science.1198687","article-title":"Innate or adaptive immunity? The example of natural killer cells","volume":"331","author":"Vivier","year":"2011","journal-title":"Science."},{"key":"2026041423510697500_bib53","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1038\/nature24029","article-title":"The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation","volume":"549","author":"Wallrapp","year":"2017","journal-title":"Nature."},{"key":"2026041423510697500_bib54","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190554","article-title":"\u03b22-adrenergic signals downregulate the innate immune response and reduce host resistance to viral infection","author":"Wieduwild","year":"2020","journal-title":"J. Exp. Med."},{"key":"2026041423510697500_bib55","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1146\/annurev.immunol.22.012703.104711","article-title":"The dynamic life of natural killer cells","volume":"22","author":"Yokoyama","year":"2004","journal-title":"Annu. Rev. Immunol."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20190549\/1766843\/jem_20190549.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20190549\/1766843\/jem_20190549.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T03:51:14Z","timestamp":1776225074000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/217\/4\/e20190549\/133715\/Cell-intrinsic-adrenergic-signaling-controls-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,11]]},"references-count":55,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,4,6]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20190549","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,11]]},"article-number":"e20190549"}}