{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:06:37Z","timestamp":1790676397241,"version":"4.1.0"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2015,10,12]],"date-time":"2015-10-12T00:00:00Z","timestamp":1444608000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Mol Immunol"],"published-print":{"date-parts":[[2016,11]]},"DOI":"10.1038\/cmi.2015.80","type":"journal-article","created":{"date-parts":[[2015,9,28]],"date-time":"2015-09-28T09:21:40Z","timestamp":1443432100000},"page":"805-815","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Effective intrahepatic CD8+ T-cell immune responses are induced by low but not high numbers of antigen-expressing hepatocytes"],"prefix":"10.1038","volume":"13","author":[{"given":"Aaron","family":"Ochel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin","family":"Cebula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Riehn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Upneet","family":"Hillebrand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Lipps","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhold","family":"Schirmbeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hansj\u00f6rg","family":"Hauser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"Wirth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,10,12]]},"reference":[{"key":"BFcmi201580_CR1","first-page":"753","volume":"10","author":"AW Thomson","year":"2010","unstructured":"Thomson AW, Knolle PA . Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev 2010; 10: 753\u2013766.","journal-title":"Nat Rev"},{"key":"BFcmi201580_CR2","first-page":"201","volume":"12","author":"U Protzer","year":"2012","unstructured":"Protzer U, Maini MK, Knolle PA . Living in the liver: hepatic infections. Nat Rev 2012; 12: 201\u2013213.","journal-title":"Nat Rev"},{"key":"BFcmi201580_CR3","doi-asserted-by":"publisher","first-page":"1745","DOI":"10.1172\/JCI39133","volume":"119","author":"B Rehermann","year":"2009","unstructured":"Rehermann B . Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J Clin Invest 2009; 119: 1745\u20131754.","journal-title":"J Clin Invest"},{"key":"BFcmi201580_CR4","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1038\/nm.3251","volume":"19","author":"B Rehermann","year":"2013","unstructured":"Rehermann B . Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat Med 2013; 19: 859\u2013868.","journal-title":"Nat Med"},{"key":"BFcmi201580_CR5","doi-asserted-by":"publisher","first-page":"2222","DOI":"10.4049\/jimmunol.1101122","volume":"187","author":"CL Day","year":"2011","unstructured":"Day CL, Abrahams DA, Lerumo L, Janse van Rensburg E, Stone L, O\u2019Rie T et al. Functional capacity of Mycobacterium tuberculosis-specific T cell responses in humans is associated with mycobacterial load. J Immunol 2011; 187: 2222\u20132232.","journal-title":"J Immunol"},{"key":"BFcmi201580_CR6","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.cell.2009.06.036","volume":"138","author":"HW Virgin","year":"2009","unstructured":"Virgin HW, Wherry EJ, Ahmed R . Redefining chronic viral infection. Cell 2009; 138: 30\u201350.","journal-title":"Cell"},{"key":"BFcmi201580_CR7","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1016\/j.immuni.2007.09.006","volume":"27","author":"EJ Wherry","year":"2007","unstructured":"Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 2007; 27: 670\u2013684.","journal-title":"Immunity"},{"key":"BFcmi201580_CR8","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.1084\/jem.188.12.2205","volume":"188","author":"AJ Zajac","year":"1998","unstructured":"Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD et al. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 1998; 188: 2205\u20132213.","journal-title":"J Exp Med"},{"key":"BFcmi201580_CR9","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 EJ, Blattman JN, 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 2003; 77: 4911\u20134927.","journal-title":"J Virol"},{"key":"BFcmi201580_CR10","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/ni.1679","volume":"10","author":"SD Blackburn","year":"2009","unstructured":"Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 2009; 10: 29\u201337.","journal-title":"Nat Immunol"},{"key":"BFcmi201580_CR11","doi-asserted-by":"publisher","first-page":"e100","DOI":"10.1371\/journal.pmed.0050100","volume":"5","author":"H Streeck","year":"2008","unstructured":"Streeck H, Brumme ZL, Anastario M, Cohen KW, Jolin JS, Meier A et al. Antigen load and viral sequence diversification determine the functional profile of HIV-1-specific CD8+ T cells. PLoS Med 2008; 5: e100.","journal-title":"PLoS Med"},{"key":"BFcmi201580_CR12","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1128\/JVI.01754-06","volume":"81","author":"CL Day","year":"2007","unstructured":"Day CL, Kiepiela P, Leslie AJ, van der Stok M, Nair K, Ismail N et al. Proliferative capacity of epitope-specific CD8 T-cell responses is inversely related to viral load in chronic human immunodeficiency virus type 1 infection. J Virol 2007; 81: 434\u2013438.","journal-title":"J Virol"},{"key":"BFcmi201580_CR13","doi-asserted-by":"publisher","first-page":"2290","DOI":"10.1002\/eji.201142275","volume":"42","author":"K Richter","year":"2012","unstructured":"Richter K, Brocker T, Oxenius A . Antigen amount dictates CD8+ T-cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell. Eur J Immunol 2012; 42: 2290\u20132304.","journal-title":"Eur J Immunol"},{"key":"BFcmi201580_CR14","doi-asserted-by":"publisher","first-page":"8623","DOI":"10.1073\/pnas.0809818106","volume":"106","author":"SN Mueller","year":"2009","unstructured":"Mueller SN, Ahmed R . High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A 2009; 106: 8623\u20138628.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"BFcmi201580_CR15","doi-asserted-by":"publisher","first-page":"1932","DOI":"10.1002\/eji.1830250721","volume":"25","author":"P Bertolino","year":"1995","unstructured":"Bertolino P, Heath WR, Hardy CL, Morahan G, Miller JF . Peripheral deletion of autoreactive CD8+ T cells in transgenic mice expressing H-2Kb in the liver. Eur J Immunol 1995; 25: 1932\u20131942.","journal-title":"Eur J Immunol"},{"key":"BFcmi201580_CR16","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1172\/JCI200421593","volume":"114","author":"DG Bowen","year":"2004","unstructured":"Bowen DG, Zen M, Holz L, Davis T, McCaughan GW, Bertolino P . The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. J Clin Invest 2004; 114: 701\u2013712.","journal-title":"J Clin Invest"},{"key":"BFcmi201580_CR17","doi-asserted-by":"publisher","first-page":"1689","DOI":"10.4049\/jimmunol.177.3.1689","volume":"177","author":"SA Wuensch","year":"2006","unstructured":"Wuensch SA, Pierce RH, Crispe IN . Local intrahepatic CD8+ T cell activation by a non-self-antigen results in full functional differentiation. J Immunol 2006; 177: 1689\u20131697.","journal-title":"J Immunol"},{"key":"BFcmi201580_CR18","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1002\/cphy.c120011","volume":"3","author":"DP Bogdanos","year":"2013","unstructured":"Bogdanos DP, Gao B, Gershwin ME . Liver immunology. Compr Physiol 2013; 3: 567\u2013598.","journal-title":"Compr Physiol"},{"key":"BFcmi201580_CR19","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1002\/hep.24508","volume":"54","author":"MR Ebrahimkhani","year":"2011","unstructured":"Ebrahimkhani MR, Mohar I, Crispe IN . Cross-presentation of antigen by diverse subsets of murine liver cells. Hepatology 2011; 54: 1379\u20131387.","journal-title":"Hepatology"},{"key":"BFcmi201580_CR20","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1038\/223472a0","volume":"223","author":"RY Calne","year":"1969","unstructured":"Calne RY, Sells RA, Pena JR, Davis DR, Millard PR, Herbertson BM et al. Induction of immunological tolerance by porcine liver allografts. Nature 1969; 223: 472\u2013476.","journal-title":"Nature"},{"key":"BFcmi201580_CR21","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.4049\/jimmunol.172.2.1009","volume":"172","author":"VG Pillarisetty","year":"2004","unstructured":"Pillarisetty VG, Shah AB, Miller G, Bleier JI, DeMatteo RP . Liver dendritic cells are less immunogenic than spleen dendritic cells because of differences in subtype composition. J Immunol 2004; 172: 1009\u20131017.","journal-title":"J Immunol"},{"key":"BFcmi201580_CR22","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1016\/j.jhep.2009.04.026","volume":"51","author":"Y Chen","year":"2009","unstructured":"Chen Y, Jiang G, Yang HR, Gu X, Wang L, Hsieh CC et al. Distinct response of liver myeloid dendritic cells to endotoxin is mediated by IL-27. J Hepatol 2009; 51: 510\u2013519.","journal-title":"J Hepatol"},{"key":"BFcmi201580_CR23","doi-asserted-by":"publisher","first-page":"2037","DOI":"10.4049\/jimmunol.174.4.2037","volume":"174","author":"A De Creus","year":"2005","unstructured":"De Creus A, Abe M, Lau AH, Hackstein H, Raimondi G, Thomson AW . Low TLR4 expression by liver dendritic cells correlates with reduced capacity to activate allogeneic T cells in response to endotoxin. J Immunol 2005; 174: 2037\u20132045.","journal-title":"J Immunol"},{"key":"BFcmi201580_CR24","first-page":"3403","volume":"118","author":"S Luth","year":"2008","unstructured":"Luth S, Huber S, Schramm C, Buch T, Zander S, Stadelmann C et al. Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. J Clin Invest 2008; 118: 3403\u20133410.","journal-title":"J Clin Invest"},{"key":"BFcmi201580_CR25","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1002\/(SICI)1521-4141(199801)28:01<221::AID-IMMU221>3.0.CO;2-F","volume":"28","author":"P Bertolino","year":"1998","unstructured":"Bertolino P, Trescol-Biemont MC, Rabourdin-Combe C . Hepatocytes induce functional activation of naive CD8+ T lymphocytes but fail to promote survival. Eur J Immunol 1998; 28: 221\u2013236.","journal-title":"Eur J Immunol"},{"key":"BFcmi201580_CR26","doi-asserted-by":"publisher","first-page":"e21847","DOI":"10.1371\/journal.pone.0021847","volume":"6","author":"K Derkow","year":"2011","unstructured":"Derkow K, Muller A, Eickmeier I, Seidel D, Rust Moreira MV, Kruse N et al. Failure of CD4 T-cells to respond to liver-derived antigen and to provide help to CD8 T-cells. PLoS One 2011; 6: e21847.","journal-title":"PLoS One"},{"key":"BFcmi201580_CR27","doi-asserted-by":"publisher","first-page":"E2540","DOI":"10.1073\/pnas.1406674111","volume":"111","author":"SS Tay","year":"2014","unstructured":"Tay SS, Wong YC, McDonald DM, Wood NA, Roediger B, Sierro F et al. Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses. Proc Natl Acad Sci USA 2014; 111: E2540\u2013E2549.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcmi201580_CR28","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1093\/nar\/gkq868","volume":"39","author":"U Sandhu","year":"2011","unstructured":"Sandhu U, Cebula M, Behme S, Riemer P, Wodarczyk C, Metzger D et al. Strict control of transgene expression in a mouse model for sensitive biological applications based on RMCE compatible ES cells. Nucleic Acids Res 2011; 39: e1.","journal-title":"Nucleic Acids Res"},{"key":"BFcmi201580_CR29","doi-asserted-by":"publisher","first-page":"e68720","DOI":"10.1371\/journal.pone.0068720","volume":"8","author":"M Cebula","year":"2013","unstructured":"Cebula M, Ochel A, Hillebrand U, Pils MC, Schirmbeck R, Hauser H et al. An inducible transgenic mouse model for immune mediated hepatitis showing clearance of antigen expressing hepatocytes by CD8+ T cells. PLoS One 2013; 8: e68720.","journal-title":"PLoS One"},{"key":"BFcmi201580_CR30","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/S0022-1759(00)00329-X","volume":"249","author":"ME Sheehy","year":"2001","unstructured":"Sheehy ME, McDermott AB, Furlan SN, Klenerman P, Nixon DF . A novel technique for the fluorometric assessment of T lymphocyte antigen specific lysis. J Immunol Methods 2001; 249: 99\u2013110.","journal-title":"J Immunol Methods"},{"key":"BFcmi201580_CR31","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1002\/gene.20039","volume":"39","author":"M Schuler","year":"2004","unstructured":"Schuler M, Dierich A, Chambon P, Metzger D . Efficient temporally controlled targeted somatic mutagenesis in hepatocytes of the mouse. Genesis 2004; 39: 167\u2013172.","journal-title":"Genesis"},{"key":"BFcmi201580_CR32","doi-asserted-by":"publisher","first-page":"1621","DOI":"10.1084\/jem.168.5.1621","volume":"168","author":"M Cebrian","year":"1988","unstructured":"Cebrian M, Yague E, Rincon M, Lopez-Botet M, de Landazuri MO, Sanchez-Madrid F . Triggering of T cell proliferation through AIM, an activation inducer molecule expressed on activated human lymphocytes. J Exp Med 1988; 168: 1621\u20131637.","journal-title":"J Exp Med"},{"key":"BFcmi201580_CR33","doi-asserted-by":"publisher","first-page":"3108","DOI":"10.1002\/1521-4141(200211)32:11<3108::AID-IMMU3108>3.0.CO;2-D","volume":"32","author":"C Castellanos Mdel","year":"2002","unstructured":"Castellanos Mdel C, Lopez-Giral S, Lopez-Cabrera M, de Landazuri MO . Multiple cis-acting elements regulate the expression of the early T cell activation antigen CD69. Eur J Immunol 2002; 32: 3108\u20133117.","journal-title":"Eur J Immunol"},{"key":"BFcmi201580_CR34","doi-asserted-by":"publisher","first-page":"e1003490","DOI":"10.1371\/journal.ppat.1003490","volume":"9","author":"M Isogawa","year":"2013","unstructured":"Isogawa M, Chung J, Murata Y, Kakimi K, Chisari FV . CD40 activation rescues antiviral CD8 (+) T cells from PD-1-mediated exhaustion. PLoS Pathog 2013; 9: e1003490.","journal-title":"PLoS Pathog"},{"key":"BFcmi201580_CR35","doi-asserted-by":"publisher","first-page":"204","DOI":"10.3109\/08820139.2012.751397","volume":"42","author":"SR Jackson","year":"2013","unstructured":"Jackson SR, Berrien-Elliott MM, Meyer JM, Wherry EJ, Teague RM . CD8+ T cell exhaustion during persistent viral infection is regulated independently of the virus-specific T cell receptor. Immunol Invest 2013; 42: 204\u2013220.","journal-title":"Immunol Invest"},{"key":"BFcmi201580_CR36","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1126\/science.1229620","volume":"338","author":"MA Paley","year":"2012","unstructured":"Paley MA, Kroy DC, Odorizzi PM, Johnnidis JB, Dolfi DV, Barnett BE et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 2012; 338: 1220\u20131225.","journal-title":"Science"},{"key":"BFcmi201580_CR37","doi-asserted-by":"publisher","first-page":"2407","DOI":"10.4049\/jimmunol.169.5.2407","volume":"169","author":"K Klugewitz","year":"2002","unstructured":"Klugewitz K, Blumenthal-Barby F, Schrage A, Knolle PA, Hamann A, Crispe IN . Immunomodulatory effects of the liver: deletion of activated CD4+ effector cells and suppression of IFN-gamma-producing cells after intravenous protein immunization. J Immunol 2002; 169: 2407\u20132413.","journal-title":"J Immunol"},{"key":"BFcmi201580_CR38","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1053\/j.gastro.2008.05.078","volume":"135","author":"LE Holz","year":"2008","unstructured":"Holz LE, Benseler V, Bowen DG, Bouillet P, Strasser A, O\u2019Reilly L et al. Intrahepatic murine CD8 T-cell activation associates with a distinct phenotype leading to Bim-dependent death. Gastroenterology 2008; 135: 989\u2013997.","journal-title":"Gastroenterology"},{"key":"BFcmi201580_CR39","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1146\/annurev.pathol.1.110304.100230","volume":"1","author":"LG Guidotti","year":"2006","unstructured":"Guidotti LG, Chisari FV . Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol 2006; 1: 23\u201361.","journal-title":"Annu Rev Pathol"},{"key":"BFcmi201580_CR40","doi-asserted-by":"publisher","first-page":"9369","DOI":"10.1128\/JVI.79.15.9369-9380.2005","volume":"79","author":"SF Wieland","year":"2005","unstructured":"Wieland SF, Chisari FV . Stealth and cunning: hepatitis B and hepatitis C viruses. J Virol 2005; 79: 9369\u20139380.","journal-title":"J Virol"},{"key":"BFcmi201580_CR41","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1038\/nature04444","volume":"439","author":"DL Barber","year":"2006","unstructured":"Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006; 439: 682\u2013687.","journal-title":"Nature"},{"key":"BFcmi201580_CR42","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1016\/j.celrep.2012.08.001","volume":"2","author":"D Wohlleber","year":"2012","unstructured":"Wohlleber D, Kashkar H, Gartner K, Frings MK, Odenthal M, Hegenbarth S et al. TNF-induced target cell killing by CTL activated through cross-presentation. Cell Rep 2012; 2: 478\u2013487.","journal-title":"Cell Rep"}],"container-title":["Cellular &amp; Molecular Immunology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/cmi201580.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/cmi201580","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/cmi201580.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T13:18:47Z","timestamp":1684415927000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/cmi201580"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10,12]]},"references-count":42,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2016,11]]}},"alternative-id":["BFcmi201580"],"URL":"https:\/\/doi.org\/10.1038\/cmi.2015.80","relation":{},"ISSN":["1672-7681","2042-0226"],"issn-type":[{"value":"1672-7681","type":"print"},{"value":"2042-0226","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,10,12]]},"assertion":[{"value":"12 February 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 July 2015","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 July 2015","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 October 2015","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}]}}