{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:57:16Z","timestamp":1791896236678,"version":"4.3.4"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,7,2]],"date-time":"2018-07-02T00:00:00Z","timestamp":1530489600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,7,2]],"date-time":"2018-07-02T00:00:00Z","timestamp":1530489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["LA1419\/5-1"],"award-info":[{"award-number":["LA1419\/5-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SI1558\/3-1"],"award-info":[{"award-number":["SI1558\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005156","name":"Alexander von Humboldt-Stiftung","doi-asserted-by":"publisher","award":["SKP2010"],"award-info":[{"award-number":["SKP2010"]}],"id":[{"id":"10.13039\/100005156","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Dysfunction of CD8<jats:sup>+<\/jats:sup> T cells can lead to the development of chronic viral infection. Identifying mechanisms responsible for such T cell dysfunction is therefore of great importance to understand how to prevent persistent viral infection. Here we show using lymphocytic choriomeningitis virus (LCMV)\u00a0infection that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is fundamental for recruiting lymphocyte-specific protein kinase (Lck) into the T cell receptor complex to form an efficient immunological synapse. CEACAM1 is essential for activation of CD8<jats:sup>+<\/jats:sup> T cells, and the absence of CEACAM1 on virus-specific CD8<jats:sup>+<\/jats:sup> T cells limits the antiviral CD8<jats:sup>+<\/jats:sup> T cell response. Treatment with anti-CEACAM1 antibody stabilizes Lck in the immunological synapse, prevents CD8<jats:sup>+<\/jats:sup> T cell exhaustion, and improves control of virus infection in vivo. Treatment of human virus-specific CD8<jats:sup>+<\/jats:sup> T cells with anti-CEACAM1 antibody similarly enhances their proliferation. We conclude that CEACAM1 is an important regulator of virus-specific CD8<jats:sup>+<\/jats:sup> T cell functions in mice and humans and represents a promising therapeutic target for modulating CD8<jats:sup>+<\/jats:sup> T cells.<\/jats:p>","DOI":"10.1038\/s41467-018-04832-2","type":"journal-article","created":{"date-parts":[[2018,6,26]],"date-time":"2018-06-26T11:42:06Z","timestamp":1530013326000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["CEACAM1 promotes CD8+ T cell responses and improves control of a chronic viral infection"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3584-7530","authenticated-orcid":false,"given":"Vishal","family":"Khairnar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Duhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwini M.","family":"Patil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilal","family":"Bhat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Thoens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1185-9534","authenticated-orcid":false,"given":"Piyush","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Adomati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah-Kim","family":"Friendrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Bezgovsek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine D.","family":"Dreesen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3313-2475","authenticated-orcid":false,"given":"Gunther","family":"Wennemuth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid M.","family":"Westendorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gennadiy","family":"Zelinskyy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulf","family":"Dittmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia","family":"Hardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Timm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim R.","family":"G\u00f6thert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp A.","family":"Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard B.","family":"Singer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl S.","family":"Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,7,2]]},"reference":[{"key":"4832_CR1","doi-asserted-by":"publisher","first-page":"2212","DOI":"10.1016\/j.vaccine.2011.12.116","volume":"30","author":"JJ Ott","year":"2012","unstructured":"Ott, J. J., Stevens, G. A., Groeger, J. & Wiersma, S. T. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 30, 2212\u20132219 (2012).","journal-title":"Vaccine"},{"key":"4832_CR2","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1016\/S0140-6736(14)62401-6","volume":"385","author":"DP Webster","year":"2015","unstructured":"Webster, D. P., Klenerman, P. & Dusheiko, G. M. Hepatitis C. Lancet 385, 1124\u20131135 (2015).","journal-title":"Lancet"},{"key":"4832_CR3","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1111\/jdv.14186","volume":"31","author":"LE Wiznia","year":"2017","unstructured":"Wiznia, L. E., Laird, M. E. & Franks, A. G. Jr. Hepatitis C virus and its cutaneous manifestations: treatment in the direct-acting antiviral era. J. Eur. Acad. Dermatol. Venereol. 31, 1260\u20131270 (2017).","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"4832_CR4","doi-asserted-by":"publisher","first-page":"e76","DOI":"10.1016\/S1473-3099(17)30482-6","volume":"18","author":"N Ford","year":"2018","unstructured":"Ford, N. et al. The WHO public health approach to HIV treatment and care: looking back and looking ahead. Lancet Infect. Dis.\u00a018, e76-e86 (2018).","journal-title":"Lancet Infect. Dis."},{"key":"4832_CR5","doi-asserted-by":"publisher","first-page":"1881","DOI":"10.1016\/S0140-6736(08)61591-3","volume":"372","author":"SP Buchbinder","year":"2008","unstructured":"Buchbinder, S. P. et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 372, 1881\u20131893 (2008).","journal-title":"Lancet"},{"key":"4832_CR6","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/nri1573","volume":"5","author":"B Rehermann","year":"2005","unstructured":"Rehermann, B. & Nascimbeni, M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat. Rev. Immunol. 5, 215\u2013229 (2005).","journal-title":"Nat. Rev. Immunol."},{"key":"4832_CR7","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/ni.2035","volume":"12","author":"EJ Wherry","year":"2011","unstructured":"Wherry, E. J. T cell exhaustion. Nat. Immunol. 12, 492\u2013499 (2011).","journal-title":"Nat. Immunol."},{"key":"4832_CR8","doi-asserted-by":"publisher","first-page":"4911","DOI":"10.1128\/JVI.77.8.4911-4927.2003","volume":"77","author":"EJ Wherry","year":"2003","unstructured":"Wherry, E. J., Blattman, J. N., Murali-Krishna, K., van der Most, R. & Ahmed, R. Viral persistence alters CD8 T cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J. Virol. 77, 4911\u20134927 (2003).","journal-title":"J. Virol."},{"key":"4832_CR9","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1038\/nri3405","volume":"13","author":"L Chen","year":"2013","unstructured":"Chen, L. & Flies, D. B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13, 227\u2013242 (2013).","journal-title":"Nat. Rev. Immunol."},{"key":"4832_CR10","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1146\/annurev.immunol.021908.132706","volume":"27","author":"JE Smith-Garvin","year":"2009","unstructured":"Smith-Garvin, J. E., Koretzky, G. A. & Jordan, M. S. T cell activation. Annu. Rev. Immunol. 27, 591\u2013619 (2009).","journal-title":"Annu. Rev. Immunol."},{"key":"4832_CR11","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1111\/j.1600-065X.2009.00767.x","volume":"229","author":"JL Riley","year":"2009","unstructured":"Riley, J. L. PD-1 signaling in primary T cells. Immunol. Rev. 229, 114\u2013125 (2009).","journal-title":"Immunol. Rev."},{"key":"4832_CR12","doi-asserted-by":"publisher","first-page":"2575","DOI":"10.1111\/j.1600-6143.2012.04224.x","volume":"12","author":"LV Riella","year":"2012","unstructured":"Riella, L. V., Paterson, A. M., Sharpe, A. H. & Chandraker, A. Role of the PD-1 pathway in the immune response. Am. J. Transplant 12, 2575\u20132587 (2012).","journal-title":"Am. J. Transplant"},{"key":"4832_CR13","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1038\/nature04444","volume":"439","author":"DL Barber","year":"2006","unstructured":"Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682\u2013687 (2006).","journal-title":"Nature"},{"key":"4832_CR14","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1056\/NEJMoa1504030","volume":"373","author":"J Larkin","year":"2015","unstructured":"Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23\u201334 (2015).","journal-title":"N. Engl. J. Med."},{"key":"4832_CR15","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/ni.1679","volume":"10","author":"SD Blackburn","year":"2009","unstructured":"Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29\u201337 (2009).","journal-title":"Nat. Immunol."},{"key":"4832_CR16","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/nri1864","volume":"6","author":"SD Gray-Owen","year":"2006","unstructured":"Gray-Owen, S. D. & Blumberg, R. S. CEACAM1: contact-dependent control of immunity. Nat. Rev. Immunol. 6, 433\u2013446 (2006).","journal-title":"Nat. Rev. Immunol."},{"key":"4832_CR17","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1189\/jlb.1202594","volume":"74","author":"G Greicius","year":"2003","unstructured":"Greicius, G., Severinson, E., Beauchemin, N., Obrink, B. & Singer, B. B. CEACAM1 is a potent regulator of B cell receptor complex-induced activation. J. Leukoc. Biol. 74, 126\u2013134 (2003).","journal-title":"J. Leukoc. Biol."},{"key":"4832_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7217","volume":"6","author":"V Khairnar","year":"2015","unstructured":"Khairnar, V. et al. CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production. Nat. Commun. 6, 6217 (2015).","journal-title":"Nat. Commun."},{"key":"4832_CR19","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/0092-8674(89)90970-7","volume":"57","author":"S Benchimol","year":"1989","unstructured":"Benchimol, S. et al. Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule. Cell 57, 327\u2013334 (1989).","journal-title":"Cell"},{"key":"4832_CR20","doi-asserted-by":"crossref","first-page":"7995","DOI":"10.1016\/S0021-9258(18)92930-3","volume":"266","author":"S Oikawa","year":"1991","unstructured":"Oikawa, S. et al. A specific heterotypic cell adhesion activity between members of carcinoembryonic antigen family, W272 and NCA, is mediated by N-domains. J. Biol. Chem. 266, 7995\u20138001 (1991).","journal-title":"J. Biol. Chem."},{"issue":"Part 3","key":"4832_CR21","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1042\/bj3200847","volume":"320","author":"I Hunter","year":"1996","unstructured":"Hunter, I., Sawa, H., Edlund, M., & Obrink, B. Evidence for regulated dimerization of cell\u2013cell adhesion molecule (C-CAM) in epithelial cells. Biochem. J. 320, 847\u2013853 (1996).","journal-title":"Biochem. J."},{"key":"4832_CR22","doi-asserted-by":"publisher","first-page":"e94106","DOI":"10.1371\/journal.pone.0094106","volume":"9","author":"BB Singer","year":"2014","unstructured":"Singer, B. B. et al. Soluble CEACAM8 interacts with CEACAM1 inhibiting TLR2-triggered immune responses. PLoS ONE 9, e94106 (2014).","journal-title":"PLoS ONE"},{"key":"4832_CR23","doi-asserted-by":"publisher","first-page":"10156","DOI":"10.1128\/JVI.78.18.10156-10165.2004","volume":"78","author":"E Hemmila","year":"2004","unstructured":"Hemmila, E. et al. Ceacam1a\u2212\/\u2212 mice are completely resistant to infection by murine coronavirus mouse hepatitis virus A59. J. Virol. 78, 10156\u201310165 (2004).","journal-title":"J. Virol."},{"key":"4832_CR24","doi-asserted-by":"publisher","first-page":"3544","DOI":"10.4049\/jimmunol.172.6.3544","volume":"172","author":"CJ Chen","year":"2004","unstructured":"Chen, C. J. & Shively, J. E. The cell\u2013cell adhesion molecule carcinoembryonic antigen-related cellular adhesion molecule 1 inhibits IL-2 production and proliferation in human T cells by association with Src homology protein-1 and down-regulates IL-2 receptor. J. Immunol. 172, 3544\u20133552 (2004).","journal-title":"J. Immunol."},{"key":"4832_CR25","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1074\/jbc.274.1.335","volume":"274","author":"M Huber","year":"1999","unstructured":"Huber, M. et al. The carboxyl-terminal region of biliary glycoprotein controls its tyrosine phosphorylation and association with protein-tyrosine phosphatases SHP-1 and SHP-2 in epithelial cells. J. Biol. Chem. 274, 335\u2013344 (1999).","journal-title":"J. Biol. Chem."},{"key":"4832_CR26","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1016\/j.immuni.2006.08.026","volume":"25","author":"T Nagaishi","year":"2006","unstructured":"Nagaishi, T. et al. SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms. Immunity 25, 769\u2013781 (2006).","journal-title":"Immunity"},{"key":"4832_CR27","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1016\/j.immuni.2012.07.016","volume":"37","author":"L Chen","year":"2012","unstructured":"Chen, L. et al. The short isoform of the CEACAM1 receptor in intestinal T cells regulates mucosal immunity and homeostasis via Tfh cell induction. Immunity 37, 930\u2013946 (2012).","journal-title":"Immunity"},{"key":"4832_CR28","doi-asserted-by":"publisher","first-page":"29654","DOI":"10.1074\/jbc.M113.504639","volume":"288","author":"PC Patel","year":"2013","unstructured":"Patel, P. C. et al. Inside-out signaling promotes dynamic changes in the carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) oligomeric state to control its cell adhesion properties. J. Biol. Chem. 288, 29654\u201329669 (2013).","journal-title":"J. Biol. Chem."},{"key":"4832_CR29","doi-asserted-by":"publisher","first-page":"3664","DOI":"10.1002\/(SICI)1521-4141(199811)28:11<3664::AID-IMMU3664>3.0.CO;2-D","volume":"28","author":"R Kammerer","year":"1998","unstructured":"Kammerer, R., Hahn, S., Singer, B. B., Luo, J. S. & von Kleist, S. Biliary glycoprotein (CD66a), a cell adhesion molecule of the immunoglobulin superfamily, on human lymphocytes: structure, expression and involvement in T cell activation. Eur. J. Immunol. 28, 3664\u20133674 (1998).","journal-title":"Eur. J. Immunol."},{"key":"4832_CR30","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1016\/j.immuni.2010.10.009","volume":"33","author":"H Pan","year":"2010","unstructured":"Pan, H. & Shively, J. E. Carcinoembryonic antigen-related cell adhesion molecule-1 regulates granulopoiesis by inhibition of granulocyte colony-stimulating factor receptor. Immunity 33, 620\u2013631 (2010).","journal-title":"Immunity"},{"key":"4832_CR31","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1189\/jlb.70.2.335","volume":"70","author":"T Chen","year":"2001","unstructured":"Chen, T. et al. Biliary glycoprotein (BGPa, CD66a, CEACAM1) mediates inhibitory signals. J. Leukoc. Biol. 70, 335\u2013340 (2001).","journal-title":"J. Leukoc. Biol."},{"key":"4832_CR32","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1038\/nature13848","volume":"517","author":"YH Huang","year":"2015","unstructured":"Huang, Y. H. et al. CEACAM1 regulates TIM3-mediated tolerance and exhaustion. Nature 517, 386\u2013390 (2015).","journal-title":"Nature"},{"key":"4832_CR33","doi-asserted-by":"publisher","first-page":"5513","DOI":"10.1242\/jcs.02660","volume":"118","author":"E Klaile","year":"2005","unstructured":"Klaile, E., M\u00fcller, M. M., Kannicht, C., Singer, B. B. & Lucka, L. CEACAM1 functionally interacts with filamin A and exerts a dual role in the regulation of cell migration. J. Cell Sci. 118, 5513\u20135524 (2005).","journal-title":"J. Cell Sci."},{"key":"4832_CR34","doi-asserted-by":"publisher","first-page":"1270","DOI":"10.1038\/ncb1492","volume":"8","author":"R Tavano","year":"2006","unstructured":"Tavano, R. et al. CD28 interaction with filamin A controls lipid raft accumulation at the T-cell immunological synapse. Nat. Cell Biol. 8, 1270\u20131276 (2006).","journal-title":"Nat. Cell Biol."},{"key":"4832_CR35","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1038\/362758a0","volume":"362","author":"D Moskophidis","year":"1993","unstructured":"Moskophidis, D., Lechner, F., Pircher, H. & Zinkernagel, R. M. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362, 758\u2013761 (1993).","journal-title":"Nature"},{"key":"4832_CR36","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/S0022-1759(03)00265-5","volume":"281","author":"MR Betts","year":"2003","unstructured":"Betts, M. R. et al. Sensitive and viable identification of antigen-specific CD8+T cells by a flow cytometric assay for degranulation. J. Immunol. Methods 281, 65\u201378 (2003).","journal-title":"J. Immunol. Methods"},{"key":"4832_CR37","doi-asserted-by":"publisher","first-page":"2626","DOI":"10.1002\/eji.1830271023","volume":"27","author":"P Seiler","year":"1997","unstructured":"Seiler, P. et al. Crucial role of marginal zone macrophages and marginal zone metallophils in the clearance of lymphocytic choriomeningitis virus infection. Eur. J. Immunol. 27, 2626\u20132633 (1997).","journal-title":"Eur. J. Immunol."},{"key":"4832_CR38","doi-asserted-by":"publisher","first-page":"e1003650","DOI":"10.1371\/journal.ppat.1003650","volume":"9","author":"N Honke","year":"2013","unstructured":"Honke, N. et al. Usp18 driven enforced viral replication in dendritic cells contributes to break of immunological tolerance in autoimmune diabetes. PLoS Pathog. 9, e1003650 (2013).","journal-title":"PLoS Pathog."},{"key":"4832_CR39","doi-asserted-by":"publisher","first-page":"5392","DOI":"10.4049\/jimmunol.173.9.5392","volume":"173","author":"R Tavano","year":"2004","unstructured":"Tavano, R. et al. CD28 and lipid rafts coordinate recruitment of Lck to the immunological synapse of human T lymphocytes. J. Immunol. 173, 5392\u20135397 (2004).","journal-title":"J. Immunol."},{"key":"4832_CR40","doi-asserted-by":"publisher","first-page":"2266","DOI":"10.1126\/science.282.5397.2266","volume":"282","author":"C Wulfing","year":"1998","unstructured":"Wulfing, C. & Davis, M. M. A receptor\/cytoskeletal movement triggered by costimulation during T cell activation. Science 282, 2266\u20132269 (1998).","journal-title":"Science"},{"key":"4832_CR41","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1126\/science.283.5402.680","volume":"283","author":"A Viola","year":"1999","unstructured":"Viola, A., Schroeder, S., Sakakibara, Y. & Lanzavecchia, A. T lymphocyte costimulation mediated by reorganization of membrane microdomains. Science 283, 680\u2013682 (1999).","journal-title":"Science"},{"key":"4832_CR42","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1016\/S1074-7613(01)00244-8","volume":"15","author":"F Michel","year":"2001","unstructured":"Michel, F., Attal-Bonnefoy, G., Mangino, G., Mise-Omata, S. & Acuto, O. CD28 as a molecular amplifier extending TCR ligation and signaling capabilities. Immunity 15, 935\u2013945 (2001).","journal-title":"Immunity"},{"key":"4832_CR43","doi-asserted-by":"publisher","first-page":"2396","DOI":"10.1128\/MCB.00165-16","volume":"36","author":"PA Thill","year":"2016","unstructured":"Thill, P. A., Weiss, A. & Chakraborty, A. K. Phosphorylation of a tyrosine residue on Zap-70 by Lck and its subsequent binding via an SH2 domain may be a key gatekeeper of T cell receptor signaling in vivo. Mol. Cell. Biol. 36, 2396\u20132402 (2016).","journal-title":"Mol. Cell. Biol."},{"key":"4832_CR44","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/0092-8674(92)90428-F","volume":"70","author":"DB Straus","year":"1992","unstructured":"Straus, D. B. & Weiss, A. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Cell 70, 585\u2013593 (1992).","journal-title":"Cell"},{"key":"4832_CR45","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1016\/j.immuni.2007.09.006","volume":"27","author":"EJ Wherry","year":"2007","unstructured":"Wherry, E. J. et al. Molecular signature of CD8+T cell exhaustion during chronic viral infection. Immunity 27, 670\u2013684 (2007).","journal-title":"Immunity"},{"key":"4832_CR46","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1111\/j.1365-2567.2010.03255.x","volume":"129","author":"JS Yi","year":"2010","unstructured":"Yi, J. S., Cox, M. A. & Zajac, A. J. T-cell exhaustion: characteristics, causes and conversion. Immunology 129, 474\u2013481 (2010).","journal-title":"Immunology"},{"key":"4832_CR47","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.it.2013.10.001","volume":"35","author":"A Schietinger","year":"2014","unstructured":"Schietinger, A. & Greenberg, P. D. Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol. 35, 51\u201360 (2014).","journal-title":"Trends Immunol."},{"key":"4832_CR48","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/nri3862","volume":"15","author":"EJ Wherry","year":"2015","unstructured":"Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486\u2013499 (2015).","journal-title":"Nat. Rev. Immunol."},{"key":"4832_CR49","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1196\/annals.1326.004","volume":"1072","author":"T Nagaishi","year":"2006","unstructured":"Nagaishi, T., Iijima, H., Nakajima, A., Chen, D. & Blumberg, R. S. Role of CEACAM1 as a regulator of T cells. Ann. NY Acad. Sci. 1072, 155\u2013175 (2006).","journal-title":"Ann. NY Acad. Sci."},{"key":"4832_CR50","doi-asserted-by":"publisher","first-page":"6085","DOI":"10.4049\/jimmunol.180.9.6085","volume":"180","author":"Z Chen","year":"2008","unstructured":"Chen, Z., Chen, L., Qiao, S. W., Nagaishi, T. & Blumberg, R. S. Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits proximal TCR signaling by targeting ZAP-70. J. Immunol. 180, 6085\u20136093 (2008).","journal-title":"J. Immunol."},{"key":"4832_CR51","doi-asserted-by":"publisher","first-page":"5139","DOI":"10.4049\/jimmunol.168.10.5139","volume":"168","author":"BB Singer","year":"2002","unstructured":"Singer, B. B. et al. Carcinoembryonic antigen-related cell adhesion molecule 1 expression and signaling in human, mouse, and rat leukocytes: evidence for replacement of the short cytoplasmic domain isoform by glycosylphosphatidylinositol-linked proteins in human leukocytes. J. Immunol. 168, 5139\u20135146 (2002).","journal-title":"J. Immunol."},{"key":"4832_CR52","doi-asserted-by":"publisher","first-page":"2257","DOI":"10.1002\/eji.1830260943","volume":"26","author":"MA Br\u00fcndler","year":"1996","unstructured":"Br\u00fcndler, M. A. et al. Immunity to viruses in B cell-deficient mice: influence of antibodies on virus persistence and on T cell memory. Eur. J. Immunol. 26, 2257\u20132262 (1996).","journal-title":"Eur. J. Immunol."},{"key":"4832_CR53","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.350","volume":"7","author":"N Shaabani","year":"2016","unstructured":"Shaabani, N. et al. CD169(+) macrophages regulate PD-L1 expression via type I interferon and thereby prevent severe immunopathology after LCMV infection. Cell Death Dis. 7, e2446 (2016).","journal-title":"Cell Death Dis."},{"key":"4832_CR54","doi-asserted-by":"publisher","first-page":"14733","DOI":"10.1073\/pnas.1009731107","volume":"107","author":"HT Jin","year":"2010","unstructured":"Jin, H. T. et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc. Natl Acad. Sci. USA 107, 14733\u201314738 (2010).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"4832_CR55","doi-asserted-by":"publisher","first-page":"e10067","DOI":"10.1371\/journal.pone.0010067","volume":"5","author":"A Gu","year":"2010","unstructured":"Gu, A., Zhang, Z., Zhang, N., Tsark, W. & Shively, J. E. Generation of human CEACAM1 transgenic mice and binding of Neisseria Opa protein to their neutrophils. PLoS ONE 5, e10067 (2010).","journal-title":"PLoS ONE"},{"key":"4832_CR56","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/0166-0934(91)90018-U","volume":"33","author":"M Battegay","year":"1991","unstructured":"Battegay, M. et al. Quantification of lymphocytic choriomeningitis virus with an immunological focus assay in 24- or 96-well plates. J. Virol. Methods 33, 191\u2013198 (1991).","journal-title":"J. Virol. Methods"},{"key":"4832_CR57","doi-asserted-by":"publisher","first-page":"10619","DOI":"10.1128\/JVI.79.16.10619-10626.2005","volume":"79","author":"G Zelinskyy","year":"2005","unstructured":"Zelinskyy, G. et al. CD8+ T-cell dysfunction due to cytolytic granule deficiency in persistent Friend retrovirus infection. J. Virol. 79, 10619\u201310626 (2005).","journal-title":"J. Virol."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-018-04832-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-018-04832-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-018-04832-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T15:11:43Z","timestamp":1671549103000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-018-04832-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,7,2]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["4832"],"URL":"https:\/\/doi.org\/10.1038\/s41467-018-04832-2","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,7,2]]},"assertion":[{"value":"7 July 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 May 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 July 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2561"}}