{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T23:42:38Z","timestamp":1788824558641,"version":"build-2803163510"},"reference-count":62,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T00:00:00Z","timestamp":1609286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and ICT","award":["NRF-2018M3A9D3079498"],"award-info":[{"award-number":["NRF-2018M3A9D3079498"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Achieving a functional cure for chronic hepatitis B virus (HBV) infection or complete elimination of HBV covalently closed circular DNA (cccDNA) has been challenging in the treatment of patients with chronic HBV infection. Although novel antivirals are being investigated, improving HBV-specific adaptive immune responses is also important for durable viral clearance. Tissue-resident memory CD8+ T (TRM) cells were recently reported as a T-cell population that resides in peripheral tissues and does not recirculate. TRM cells have been studied in the livers of mice and humans. Liver TRM cells have distinct characteristics compared to T cells in peripheral blood or other tissues, which may be associated with the unique microenvironment of the liver. In this review, we describe the characteristics of liver TRM cells and their implications in chronic HBV infection. We emphasize that liver TRM cells can be an immunotherapeutic target for the treatment of chronic HBV infection.<\/jats:p>","DOI":"10.3390\/ijms22010283","type":"journal-article","created":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T09:35:23Z","timestamp":1609320923000},"page":"283","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Liver-Resident Memory CD8+ T Cells: Possible Roles in Chronic HBV Infection"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1456-1450","authenticated-orcid":false,"given":"Ji Won","family":"Han","sequence":"first","affiliation":[{"name":"Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea"},{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul St. Mary\u2019s Hospital, Seoul 06591, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6308-9503","authenticated-orcid":false,"given":"Eui-Cheol","family":"Shin","sequence":"additional","affiliation":[{"name":"Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1016\/S0140-6736(18)31865-8","article-title":"Chronic hepatitis B virus infection","volume":"392","author":"Seto","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/S2468-1253(19)30119-0","article-title":"A global scientific strategy to cure hepatitis B","volume":"4","author":"Revill","year":"2019","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/nri.2016.69","article-title":"Immune responses and immunopathology in acute and chronic viral hepatitis","volume":"16","author":"Shin","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1038\/s41575-019-0196-9","article-title":"Restoring, releasing or replacing adaptive immunity in chronic hepatitis B","volume":"16","author":"Maini","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S71","DOI":"10.1016\/j.jhep.2016.01.026","article-title":"Adaptive immunity in HBV infection","volume":"64","author":"Bertoletti","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1053\/j.gastro.2009.09.052","article-title":"Antiviral Intrahepatic T-Cell Responses Can Be Restored by Blocking Programmed Death-1 Pathway in Chronic Hepatitis B","volume":"138","author":"Fisicaro","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4573","DOI":"10.1172\/JCI121957","article-title":"PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection","volume":"128","author":"Salimzadeh","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.jhep.2019.06.028","article-title":"Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study","volume":"71","author":"Gane","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.it.2016.11.004","article-title":"Transcriptional Regulation of Tissue-Resident Lymphocytes","volume":"38","author":"Mackay","year":"2017","journal-title":"Trends Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/nri.2015.3","article-title":"Tissue-resident memory T cells: Local specialists in immune defence","volume":"16","author":"Mueller","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.immuni.2014.12.007","article-title":"Tissue-resident memory T cells","volume":"41","author":"Schenkel","year":"2014","journal-title":"Immunity"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1146\/annurev-immunol-051116-052415","article-title":"Immune Responses in the Liver","volume":"36","author":"Kubes","year":"2018","journal-title":"Annu. Rev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/S1074-7613(04)00103-7","article-title":"Dynamics of blood-borne CD8 memory T cell migration in vivo","volume":"20","author":"Klonowski","year":"2004","journal-title":"Immunity"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nature10851","article-title":"Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity","volume":"483","author":"Jiang","year":"2012","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.cell.2015.03.031","article-title":"Quantifying Memory CD8 T Cells Reveals Regionalization of Immunosurveillance","volume":"161","author":"Steinert","year":"2015","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2702","DOI":"10.4049\/jimmunol.1201682","article-title":"Cutting edge: Intravascular staining redefines lung CD8 T cell responses","volume":"189","author":"Anderson","year":"2012","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1126\/science.aad2035","article-title":"Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes","volume":"352","author":"Mackay","year":"2016","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/j.immuni.2016.08.011","article-title":"Liver-Resident Memory CD8(+) T Cells Form a Front-Line Defense against Malaria Liver-Stage Infection","volume":"45","author":"Ng","year":"2016","journal-title":"Immunity"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"749","DOI":"10.4049\/jimmunol.1601500","article-title":"TGF-beta Controls the Formation of Kidney-Resident T Cells via Promoting Effector T Cell Extravasation","volume":"198","author":"Ma","year":"2017","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/s41423-019-0359-1","article-title":"Local heroes or villains: Tissue-resident memory T cells in human health and disease","volume":"17","author":"Sasson","year":"2020","journal-title":"Cell. Mol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5307","DOI":"10.1073\/pnas.1322292111","article-title":"Persistence of skin-resident memory T cells within an epidermal niche","volume":"111","author":"Zaid","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1038\/ni.2744","article-title":"The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin","volume":"14","author":"Mackay","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1126\/science.1254536","article-title":"T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses","volume":"346","author":"Schenkel","year":"2014","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1034\/j.1600-0528.2002.017412.x","article-title":"The liver as a site of T-cell apoptosis: Graveyard, or killing field?","volume":"174","author":"Crispe","year":"2000","journal-title":"Immunol. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.cell.2015.03.005","article-title":"Immunosurveillance of the liver by intravascular effector CD8(+) T cells","volume":"161","author":"Guidotti","year":"2015","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1002\/hep.24352","article-title":"Murine hepatic stellate cells veto CD8 T cell activation by a CD54-dependent mechanism","volume":"54","author":"Schildberg","year":"2011","journal-title":"Hepatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1002\/hep.20488","article-title":"Inhibition of T-cell responses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice","volume":"40","author":"Yu","year":"2004","journal-title":"Hepatology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.4049\/jimmunol.1201937","article-title":"Hepatic stellate cells preferentially induce Foxp3+ regulatory T cells by production of retinoic acid","volume":"190","author":"Dunham","year":"2013","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/hep.27793","article-title":"Liver inflammation abrogates immunological tolerance induced by Kupffer cells","volume":"62","author":"Heymann","year":"2015","journal-title":"Hepatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1002\/hep.22395","article-title":"Mechanism of T cell tolerance induction by murine hepatic Kupffer cells","volume":"48","author":"You","year":"2008","journal-title":"Hepatology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1016\/S0016-5085(99)70508-1","article-title":"Induction of cytokine production in naive CD4(+) T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells","volume":"116","author":"Knolle","year":"1999","journal-title":"Gastroenterology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.jhep.2012.09.008","article-title":"Inhibition of inflammatory CD4 T cell activity by murine liver sinusoidal endothelial cells","volume":"58","author":"Carambia","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1038\/82161","article-title":"Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance","volume":"6","author":"Limmer","year":"2000","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1002\/hep.21965","article-title":"Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance","volume":"47","author":"Diehl","year":"2008","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1053\/j.gastro.2008.05.078","article-title":"Intrahepatic murine CD8 T-cell activation associates with a distinct phenotype leading to Bim-dependent death","volume":"135","author":"Holz","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/gene.2013.20","article-title":"Unique transcriptional profile of liver-resident memory CD8+ T cells induced by immunization with malaria sporozoites","volume":"14","author":"Tse","year":"2013","journal-title":"Genes Immun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1093\/infdis\/jiu281","article-title":"The chemokine receptor CXCR6 is required for the maintenance of liver memory CD8(+) T cells specific for infectious pathogens","volume":"210","author":"Tse","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"McNamara, H.A., Cai, Y., Wagle, M.V., Sontani, Y., Roots, C.M., Miosge, L.A., O\u2019Connor, J.H., Sutton, H.J., Ganusov, V.V., and Heath, W.R. (2017). Up-regulation of LFA-1 allows liver-resident memory T cells to patrol and remain in the hepatic sinusoids. Sci. Immunol., 2.","DOI":"10.1126\/sciimmunol.aaj1996"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.celrep.2018.08.094","article-title":"CD8(+) T Cell Activation Leads to Constitutive Formation of Liver Tissue-Resident Memory T Cells that Seed a Large and Flexible Niche in the Liver","volume":"25","author":"Holz","year":"2018","journal-title":"Cell Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6172","DOI":"10.1038\/s41598-017-06352-3","article-title":"Human intrahepatic CD69 + CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity","volume":"7","author":"Stelma","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1084\/jem.20162115","article-title":"IL-2(high) tissue-resident T cells in the human liver: Sentinels for hepatotropic infection","volume":"214","author":"Pallett","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.4049\/jimmunol.174.2.1055","article-title":"CXC chemokine ligand 16 promotes integrin-mediated adhesion of liver-infiltrating lymphocytes to cholangiocytes and hepatocytes within the inflamed human liver","volume":"174","author":"Heydtmann","year":"2005","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5226","DOI":"10.4049\/jimmunol.1202909","article-title":"Chemokine Receptor CXCR6-Dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis","volume":"190","author":"Wehr","year":"2013","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4007","DOI":"10.1128\/IAI.73.7.4007-4016.2005","article-title":"Involvement of up-regulated CXC chemokine ligand 16\/scavenger receptor that binds phosphatidylserine and oxidized lipoprotein in endotoxin-induced lethal liver injury via regulation of T-cell recruitment and adhesion","volume":"73","author":"Xu","year":"2005","journal-title":"Infect Immun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.immuni.2018.12.024","article-title":"Liver-Resident NK Cells Control Antiviral Activity of Hepatic T Cells via the PD-1-PD-L1 Axis","volume":"50","author":"Zhou","year":"2019","journal-title":"Immunity"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/j.jhep.2020.01.010","article-title":"Functions of human liver CD69(+)CD103(-)CD8(+) T cells depend on HIF-2alpha activity in healthy and pathologic livers","volume":"72","author":"Kim","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/j.jhep.2020.02.001","article-title":"Liver-resident CD8+ T cells: Learning lessons from the local experts","volume":"72","author":"Swadling","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.immuni.2017.11.025","article-title":"Innate-like Cytotoxic Function of Bystander-Activated CD8(+) T Cells Is Associated with Liver Injury in Acute Hepatitis A","volume":"48","author":"Kim","year":"2018","journal-title":"Immunity"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1111\/j.1582-4934.2011.01258.x","article-title":"Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia","volume":"15","author":"Carreau","year":"2011","journal-title":"J. Cell. Mol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1038\/ni.2714","article-title":"Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen","volume":"14","author":"Doedens","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.molimm.2015.08.004","article-title":"Hypoxia-inducible factors regulate T cell metabolism and function","volume":"68","author":"Phan","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.immuni.2013.12.010","article-title":"Immune responses to HCV and other hepatitis viruses","volume":"40","author":"Park","year":"2014","journal-title":"Immunity"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4215","DOI":"10.1128\/JVI.02844-06","article-title":"Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection","volume":"81","author":"Boni","year":"2007","journal-title":"J. Virol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1038\/nm.3251","article-title":"Pathogenesis of chronic viral hepatitis: Differential roles of T cells and NK cells","volume":"19","author":"Rehermann","year":"2013","journal-title":"Nat. Med."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Fumagalli, V., Di Lucia, P., Venzin, V., Bono, E.B., Jordan, R., Frey, C.R., Delaney, W., Chisari, F.V., Guidotti, L.G., and Iannacone, M. (2020). Serum HBsAg clearance has minimal impact on CD8+ T cell responses in mouse models of HBV infection. J. Exp. Med., 217.","DOI":"10.1084\/jem.20200298"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/S0168-8278(03)00292-7","article-title":"Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B","volume":"39","author":"Boni","year":"2003","journal-title":"J. Hepatol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.jhep.2019.09.031","article-title":"CXCL13-mediated recruitment of intrahepatic CXCR5(+)CD8(+) T cells favors viral control in chronic HBV infection","volume":"72","author":"Li","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41586-019-1620-6","article-title":"Dynamics and genomic landscape of CD8(+) T cells undergoing hepatic priming","volume":"574","author":"Benechet","year":"2019","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1084\/jem.20170842","article-title":"Tissue-resident T cells in hepatitis B: A new target for cure?","volume":"214","author":"Bolte","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Naggie, S., and Lok, A.S. (2020). New Therapeutics for Hepatitis B: The Road to Cure. Annu. Rev. Med.","DOI":"10.1146\/annurev-med-080119-103356"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1053\/j.gastro.2015.09.026","article-title":"Interferon-gamma and Tumor Necrosis Factor-alpha Produced by T Cells Reduce the HBV Persistence Form, cccDNA, Without Cytolysis","volume":"150","author":"Xia","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1038\/s41591-018-0078-7","article-title":"Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis","volume":"24","author":"Savas","year":"2018","journal-title":"Nat. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/283\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:47:43Z","timestamp":1760179663000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/283"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,30]]},"references-count":62,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["ijms22010283"],"URL":"https:\/\/doi.org\/10.3390\/ijms22010283","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,30]]}}}