{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T11:18:13Z","timestamp":1776770293992,"version":"3.51.2"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2018,5,1]],"date-time":"2018-05-01T00:00:00Z","timestamp":1525132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Natural killer cells are critical in the immune response to infection and malignancy. Prior studies have demonstrated that Crk family proteins can influence cell apoptosis, proliferation, and cell transformation. In this study, we investigated the role of Crk family proteins in mouse NK cell differentiation and host defense using a mouse CMV infection model. The number of NK cells, maturational state, and the majority of the NKR repertoire was similar in Crk x Crk-like (CrkL)\u2013double-deficient and wild type NK cells. However, Crk family proteins were required for optimal activation, IFN-\u03b3 production, expansion, and differentiation of Ly49H+ NK cells, as well as host defense during mouse CMV infection. The diminished function of Crk x CrkL\u2013double-deficient NK cells correlated with decreased phosphorylation of STAT4 and STAT1 in response to IL-12 and IFN-\u03b1 stimulation, respectively. Together, our findings analyzing NK cell\u2013specific Crk-deficient mice provide insights into the role of Crk family proteins in NK cell function and host defense.<\/jats:p>","DOI":"10.4049\/jimmunol.1701639","type":"journal-article","created":{"date-parts":[[2018,4,4]],"date-time":"2018-04-04T15:40:34Z","timestamp":1522856434000},"page":"3420-3428","source":"Crossref","is-referenced-by-count":14,"title":["Crk Adaptor Proteins Regulate NK Cell Expansion and Differentiation during Mouse Cytomegalovirus Infection"],"prefix":"10.1093","volume":"200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8386-3607","authenticated-orcid":false,"given":"Tsukasa","family":"Nabekura","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of California , San Francisco, San Francisco, CA 94143"},{"name":"Parker Institute for Cancer Immunotherapy , San Francisco, CA 94143"},{"name":"Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba , Ibaraki 305-8577,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiying","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Inflammation and Epigenetics, Houston Methodist Research Institute , Houston, TX 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Casey","family":"Schroeder","sequence":"additional","affiliation":[{"name":"Center for Inflammation and Epigenetics, Houston Methodist Research Institute , Houston, TX 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3897-3994","authenticated-orcid":false,"given":"Taeju","family":"Park","sequence":"additional","affiliation":[{"name":"Children\u2019s Research Institute, Children\u2019s Mercy Kansas City , Kansas City, MO 64108"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7022-8287","authenticated-orcid":false,"given":"Eric","family":"Vivier","sequence":"additional","affiliation":[{"name":"Centre d\u2019Immunologie de Marseille-Luminy, Aix Marseille Universit\u00e9, INSERM, CNRS , 13288 Marseille,","place":["France"]},{"name":"Service d\u2019Immunologie, H\u00f4pital de la Timone, Assistance Publique-H\u00f4pitaux de Marseille , 13288 Marseille,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1308-3952","authenticated-orcid":false,"given":"Lewis L","family":"Lanier","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of California , San Francisco, San Francisco, CA 94143"},{"name":"Parker Institute for Cancer Immunotherapy , San Francisco, CA 94143"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongfang","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Inflammation and Epigenetics, Houston Methodist Research Institute , Houston, TX 77030"},{"name":"Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University , New York, NY 10065"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2018,5,15]]},"reference":[{"key":"2025030610150089700_r1","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.coi.2016.11.003","article-title":"NK cells in host responses to viral infections","volume":"44","author":"Lam","year":"2017","journal-title":"Curr. Opin. Immunol."},{"key":"2025030610150089700_r2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/nrc.2015.5","article-title":"NK cells and cancer: you can teach innate cells new tricks","volume":"16","author":"Morvan","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"2025030610150089700_r3","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.coi.2008.03.005","article-title":"Line of attack: NK cell specificity and integration of signals","volume":"20","author":"Bryceson","year":"2008","journal-title":"Curr. Opin. Immunol."},{"key":"2025030610150089700_r4","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/j.0105-2896.2010.00904.x","article-title":"Cytotoxic immunological synapses","volume":"235","author":"Dustin","year":"2010","journal-title":"Immunol. Rev."},{"key":"2025030610150089700_r5","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.immuni.2009.05.009","article-title":"Integrin-dependent organization and bidirectional vesicular traffic at cytotoxic immune synapses","volume":"31","author":"Liu","year":"2009","journal-title":"Immunity"},{"key":"2025030610150089700_r6","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.immuni.2012.03.007","article-title":"The adaptor protein Crk controls activation and inhibition of natural killer cells","volume":"36","author":"Liu","year":"2012","journal-title":"Immunity"},{"key":"2025030610150089700_r7","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/icb.2013.64","article-title":"The adaptor protein Crk in immune response","volume":"92","author":"Liu","year":"2014","journal-title":"Immunol. Cell Biol."},{"key":"2025030610150089700_r8","doi-asserted-by":"crossref","first-page":"6348","DOI":"10.1038\/sj.onc.1204779","article-title":"Crk family adaptors-signalling complex formation and biological roles","volume":"20","author":"Feller","year":"2001","journal-title":"Oncogene"},{"key":"2025030610150089700_r9","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1478-811X-7-13","article-title":"Crk and CrkL adaptor proteins: networks for physiological and pathological signaling","volume":"7","author":"Birge","year":"2009","journal-title":"Cell Commun. Signal."},{"key":"2025030610150089700_r10","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/ncb2395","article-title":"The adaptor protein CRK is a pro-apoptotic transducer of endoplasmic reticulum stress","volume":"14","author":"Austgen","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"2025030610150089700_r11","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1002\/j.1460-2075.1994.tb06518.x","article-title":"c-Abl kinase regulates the protein binding activity of c-Crk","volume":"13","author":"Feller","year":"1994","journal-title":"EMBO J."},{"key":"2025030610150089700_r12","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.immuni.2008.07.014","article-title":"Inhibitory receptor signaling via tyrosine phosphorylation of the adaptor Crk","volume":"29","author":"Peterson","year":"2008","journal-title":"Immunity"},{"key":"2025030610150089700_r13","doi-asserted-by":"crossref","first-page":"6933","DOI":"10.4049\/jimmunol.0803840","article-title":"PI3K links NKG2D signaling to a CrkL pathway involved in natural killer cell adhesion, polarity, and granule secretion","volume":"182","author":"Segovis","year":"2009","journal-title":"J. Immunol."},{"key":"2025030610150089700_r14","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/j.jaci.2015.01.011","article-title":"Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome","volume":"135","author":"Zheng","year":"2015","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030610150089700_r15","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1006\/clin.1997.4463","article-title":"Lack of correlation between impaired T cell production, immunodeficiency, and other phenotypic features in chromosome 22q11.2 deletion syndromes","volume":"86","author":"Sullivan","year":"1998","journal-title":"Clin. Immunol. Immunopathol."},{"key":"2025030610150089700_r16","doi-asserted-by":"crossref","first-page":"322","DOI":"10.3389\/fimmu.2013.00322","article-title":"Immunodeficiency in DiGeorge syndrome and options for treating cases with complete athymia","volume":"4","author":"Davies","year":"2013","journal-title":"Front. Immunol."},{"key":"2025030610150089700_r17","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.jaip.2013.08.003","article-title":"The diverse clinical features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome)","volume":"1","author":"Maggadottir","year":"2013","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"2025030610150089700_r18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/MD.0b013e3182060469","article-title":"Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome\/velocardiofacial syndrome)","volume":"90","author":"McDonald-McGinn","year":"2011","journal-title":"Medicine (Baltimore)"},{"key":"2025030610150089700_r19","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1016\/j.amjcard.2010.01.333","article-title":"Cardiovascular anomalies associated with chromosome 22q11.2 deletion syndrome","volume":"105","author":"Momma","year":"2010","journal-title":"Am. J. Cardiol."},{"key":"2025030610150089700_r20","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1038\/85845","article-title":"DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1","volume":"27","author":"Jerome","year":"2001","journal-title":"Nat. Genet."},{"key":"2025030610150089700_r21","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.devcel.2005.12.002","article-title":"Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome","volume":"10","author":"Guris","year":"2006","journal-title":"Dev. Cell"},{"key":"2025030610150089700_r22","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/85855","article-title":"Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome","volume":"27","author":"Guris","year":"2001","journal-title":"Nat. Genet."},{"key":"2025030610150089700_r23","doi-asserted-by":"crossref","first-page":"17115","DOI":"10.1073\/pnas.0805239105","article-title":"Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development","volume":"105","author":"Newbern","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030610150089700_r24","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.devcel.2005.12.003","article-title":"Crkl deficiency disrupts Fgf8 signaling in a mouse model of 22q11 deletion syndromes","volume":"10","author":"Moon","year":"2006","journal-title":"Dev. Cell"},{"key":"2025030610150089700_r25","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.jaci.2015.10.051","article-title":"Reduction of CRKL expression in patients with partial DiGeorge syndrome is associated with impairment of T-cell functions","volume":"138","author":"Giacomelli","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030610150089700_r26","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00018-011-0842-z","article-title":"Immunological aspects of 22q11.2 deletion syndrome","volume":"69","author":"Gennery","year":"2012","journal-title":"Cell. Mol. Life Sci."},{"key":"2025030610150089700_r27"},{"key":"2025030610150089700_r28","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1111\/j.1399-3038.2006.00409.x","article-title":"Humoral immune responses and CD27+ B cells in children with DiGeorge syndrome (22q11.2 deletion syndrome)","volume":"17","author":"Finocchi","year":"2006","journal-title":"Pediatr. Allergy Immunol."},{"key":"2025030610150089700_r29","doi-asserted-by":"crossref","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":"2025030610150089700_r30","doi-asserted-by":"crossref","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":"2025030610150089700_r31","doi-asserted-by":"crossref","first-page":"6272","DOI":"10.1128\/MCB.00472-06","article-title":"Cardiovascular and craniofacial defects in Crk-null mice","volume":"26","author":"Park","year":"2006","journal-title":"Mol. Cell Biol."},{"key":"2025030610150089700_r32","doi-asserted-by":"crossref","first-page":"13551","DOI":"10.1523\/JNEUROSCI.4323-08.2008","article-title":"Crk and Crk-like play essential overlapping roles downstream of disabled-1 in the Reelin pathway","volume":"28","author":"Park","year":"2008","journal-title":"J. Neurosci."},{"key":"2025030610150089700_r33","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/nature07665","article-title":"Adaptive immune features of natural killer cells. [Published erratum appears in 2009 Nature 457: 1168.]","volume":"457","author":"Sun","year":"2009","journal-title":"Nature"},{"key":"2025030610150089700_r34","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/978-1-62703-496-8_24","article-title":"Generation of bone marrow and fetal liver chimeric mice","volume":"1032","author":"Holl","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"2025030610150089700_r35","doi-asserted-by":"crossref","first-page":"7360","DOI":"10.1073\/pnas.82.21.7360","article-title":"Cloning of Ly-5 cDNA","volume":"82","author":"Shen","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030610150089700_r36","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.immuni.2013.12.011","article-title":"Costimulatory molecule DNAM-1 is essential for optimal differentiation of memory natural killer cells during mouse cytomegalovirus infection","volume":"40","author":"Nabekura","year":"2014","journal-title":"Immunity"},{"key":"2025030610150089700_r37","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1084\/jem.20140798","article-title":"Antigen-specific expansion and differentiation of natural killer cells by alloantigen stimulation","volume":"211","author":"Nabekura","year":"2014","journal-title":"J. Exp. Med."},{"key":"2025030610150089700_r38","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.virusres.2003.08.009","article-title":"Improved detection and quantification of mouse cytomegalovirus by real-time PCR","volume":"98","author":"Vliegen","year":"2003","journal-title":"Virus Res."},{"key":"2025030610150089700_r39","doi-asserted-by":"crossref","first-page":"5948","DOI":"10.4049\/jimmunol.1500424","article-title":"IL-33 receptor ST2 amplifies the expansion of NK cells and enhances host defense during mouse cytomegalovirus infection","volume":"194","author":"Nabekura","year":"2015","journal-title":"J. Immunol."},{"key":"2025030610150089700_r40","doi-asserted-by":"crossref","first-page":"2669","DOI":"10.1084\/jem.20141172","article-title":"Cytomegalovirus generates long-lived antigen-specific NK cells with diminished bystander activation to heterologous infection","volume":"211","author":"Min-Oo","year":"2014","journal-title":"J. Exp. Med."},{"key":"2025030610150089700_r41","doi-asserted-by":"crossref","first-page":"7536","DOI":"10.1128\/JVI.78.14.7536-7544.2004","article-title":"Gain of virulence caused by loss of a gene in murine cytomegalovirus","volume":"78","author":"Bubi\u0107","year":"2004","journal-title":"J. Virol."},{"key":"2025030610150089700_r42","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/0968-0004(94)90129-5","article-title":"SH2 and SH3 domains as molecular adhesives: the interactions of Crk and Abl","volume":"19","author":"Feller","year":"1994","journal-title":"Trends Biochem. Sci."},{"key":"2025030610150089700_r43","first-page":"F201","article-title":"Signal transduction by wild-type and leukemogenic Abl proteins","volume":"1333","author":"Raitano","year":"1997","journal-title":"Biochim. Biophys. Acta"},{"key":"2025030610150089700_r44","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/sji.12574","article-title":"The Abl-1 kinase is dispensable for NK cell inhibitory signaling and is not involved in murine NK cell education","volume":"86","author":"Ganesan","year":"2017","journal-title":"Scand. J. Immunol."},{"key":"2025030610150089700_r45","doi-asserted-by":"crossref","first-page":"21365","DOI":"10.1074\/jbc.271.35.21365","article-title":"A potential SH3 domain-binding site in the Crk SH2 domain","volume":"271","author":"Anafi","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2025030610150089700_r46","doi-asserted-by":"crossref","first-page":"22925","DOI":"10.1016\/S0021-9258(17)31596-X","article-title":"Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia","volume":"269","author":"Oda","year":"1994","journal-title":"J. Biol. Chem."},{"key":"2025030610150089700_r47","doi-asserted-by":"crossref","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":"2025030610150089700_r48","doi-asserted-by":"crossref","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":"2025030610150089700_r49","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1084\/jem.20070401","article-title":"High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells","volume":"204","author":"Miyagi","year":"2007","journal-title":"J. Exp. Med."},{"key":"2025030610150089700_r50","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1016\/j.jaci.2014.06.006","article-title":"Intact IL-12 signaling is necessary for the generation of human natural killer cells with enhanced effector function after restimulation","volume":"134","author":"Simhadri","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030610150089700_r51","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1074\/jbc.274.2.571","article-title":"Activation of a CrkL-stat5 signaling complex by type I interferons","volume":"274","author":"Fish","year":"1999","journal-title":"J. Biol. Chem."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/200\/10\/3420\/62231983\/ji1701639.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/200\/10\/3420\/62231983\/ji1701639.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T10:44:40Z","timestamp":1741257880000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/200\/10\/3420\/7966074"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5]]},"references-count":51,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2018,5,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1701639","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,5]]},"published":{"date-parts":[[2018,5]]}}}