{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T22:53:54Z","timestamp":1783810434076,"version":"3.55.0"},"reference-count":113,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T00:00:00Z","timestamp":1636588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hallym University Research Fund","award":["Hallym University Research Fund"],"award-info":[{"award-number":["Hallym University Research Fund"]}]},{"name":"Basic Science 410 Research Program through the National Research Foundation of Korea funded by the Ministry of 411 Education, Science and Technology","award":["NRF-2018M3A9F3020956, NRF-2019R1I1A3A01060447, 412 NRF-2020R1I1A3073530 and NRF-2020R1A6A1A03043026"],"award-info":[{"award-number":["NRF-2018M3A9F3020956, NRF-2019R1I1A3A01060447, 412 NRF-2020R1I1A3073530 and NRF-2020R1A6A1A03043026"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by hepatic accumulation of excess lipids. T cells are commonly classified into various subsets based on their surface markers including T cell receptors, type of antigen presentation and pathophysiological functions. Several studies have implicated various T cell subsets and natural killer (NK) cells in the progression of NAFLD. While NK cells are mainly components of the innate hepatic immune system, the majority of T cell subsets can be part of both the adaptive and innate systems. Several studies have reported that various stages of NAFLD are accompanied by the accumulation of distinct T cell subsets and NK cells with different functions and phenotypes observed usually resulting in proinflammatory effects. More importantly, the overall stimulation of the intrahepatic T cell subsets is directly influenced by the homeostasis of the gut microbiota. Similarly, NK cells have been found to accumulate in the liver in response to pathogens and tumors. In this review, we discussed the nature and pathophysiological roles of T cell subsets including \u03b3\u03b4 T cells, NKT cells, Mucosal-associated invariant T (MAIT) cells as well as NK cells in NAFLD.<\/jats:p>","DOI":"10.3390\/ijms222212190","type":"journal-article","created":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T23:02:41Z","timestamp":1636671761000},"page":"12190","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5133-3620","authenticated-orcid":false,"given":"Yoseph Asmelash","family":"Gebru","sequence":"first","affiliation":[{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6008-1143","authenticated-orcid":false,"given":"Haripriya","family":"Gupta","sequence":"additional","affiliation":[{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeong Seop","family":"Kim","sequence":"additional","affiliation":[{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung A.","family":"Eom","sequence":"additional","affiliation":[{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goo Hyun","family":"Kwon","sequence":"additional","affiliation":[{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4251-2739","authenticated-orcid":false,"given":"Eunju","family":"Park","sequence":"additional","affiliation":[{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Ju","family":"Jeong","sequence":"additional","affiliation":[{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Min","family":"Won","sequence":"additional","affiliation":[{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satya Priya","family":"Sharma","sequence":"additional","affiliation":[{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3060-6217","authenticated-orcid":false,"given":"Raja","family":"Ganesan","sequence":"additional","affiliation":[{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5792-1500","authenticated-orcid":false,"given":"Dong Joon","family":"Kim","sequence":"additional","affiliation":[{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9206-9245","authenticated-orcid":false,"given":"Ki Tae","family":"Suk","sequence":"additional","affiliation":[{"name":"Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.2147\/CIA.S170533","article-title":"Novel insights into the relationship between nonalcoholic fatty liver disease and osteoporosis","volume":"13","author":"Filip","year":"2018","journal-title":"Clin. Interv. Aging"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.jhepr.2019.07.002","article-title":"From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options","volume":"1","author":"Gastaldelli","year":"2019","journal-title":"JHEP Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"149","DOI":"10.3389\/fneur.2012.00149","article-title":"Obstructive sleep apnea and non-alcoholic Fatty liver disease: Is the liver another target?","volume":"3","author":"Mirrakhimov","year":"2012","journal-title":"Front. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8351","DOI":"10.3748\/wjg.v20.i26.8351","article-title":"Nonalcoholic fatty liver disease and polycystic ovary syndrome","volume":"20","author":"Vassilatou","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nrgastro.2015.200","article-title":"Immunology in the liver--from homeostasis to disease","volume":"13","author":"Heymann","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1038\/ni.2691","article-title":"Immune surveillance by the liver","volume":"14","author":"Jenne","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3389\/fimmu.2014.00177","article-title":"Role of innate immune response in non-alcoholic Fatty liver disease: Metabolic complications and therapeutic tools","volume":"5","author":"Meli","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4301","DOI":"10.1096\/fj.11-189472","article-title":"Kupffer cell depletion prevents but has no therapeutic effect on metabolic and inflammatory changes induced by a high-fat diet","volume":"25","author":"Lanthier","year":"2011","journal-title":"FASEB J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1002\/hep.23599","article-title":"Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease","volume":"51","author":"Syn","year":"2010","journal-title":"Hepatology"},{"key":"ref_11","first-page":"322","article-title":"Revisiting the Role of Natural Killer Cells in Non-Alcoholic Fatty Liver Disease","volume":"12","author":"Delgado","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"82","DOI":"10.3389\/fimmu.2019.00082","article-title":"The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity","volume":"10","author":"Weyler","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1042\/CS20160005","article-title":"Adipose tissue inflammation: A cause or consequence of obesity-related insulin resistance?","volume":"130","author":"Bluher","year":"2016","journal-title":"Clin. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"19867","DOI":"10.3390\/ijms141019867","article-title":"Immunological mechanisms in the pathophysiology of non-alcoholic steatohepatitis","volume":"14","author":"Vonghia","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"147","DOI":"10.4110\/in.2016.16.3.147","article-title":"The Immune Landscape in Nonalcoholic Steatohepatitis","volume":"16","author":"Narayanan","year":"2016","journal-title":"Immune. Netw."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1038\/ni.2705","article-title":"Tissue-resident macrophages","volume":"14","author":"Davies","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_17","first-page":"91","article-title":"MHC and T cell development","volume":"1","author":"Viret","year":"1999","journal-title":"Rev. Immunogenet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1146\/annurev-immunol-032414-112334","article-title":"T cell antigen receptor recognition of antigen-presenting molecules","volume":"33","author":"Rossjohn","year":"2015","journal-title":"Annu. Rev. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1159\/000019128","article-title":"The human T cell receptor alpha variable (TRAV) genes","volume":"17","author":"Scaviner","year":"2000","journal-title":"Exp. Clin. Immunogenet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1002\/pro.2412","article-title":"The versatility of the alphabeta T-cell antigen receptor","volume":"23","author":"Bhati","year":"2014","journal-title":"Protein. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nri3384","article-title":"Six-of-the-best: Unique contributions of gammadelta T cells to immunology","volume":"13","author":"Vantourout","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/ni1095","article-title":"CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse","volume":"5","author":"Li","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S1074-7613(03)00019-0","article-title":"Quantitative analysis of the contribution of TCR\/pepMHC affinity and CD8 to T cell activation","volume":"18","author":"Holler","year":"2003","journal-title":"Immunity"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/nature01433","article-title":"Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1","volume":"422","author":"Treiner","year":"2003","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1016\/S1357-2725(03)00037-2","article-title":"T lymphocytes","volume":"35","author":"Fabbri","year":"2003","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1146\/annurev.immunol.18.1.975","article-title":"\u03b3\u03b4 cells: A right time and a right place for a conserved third way of protection","volume":"18","author":"Hayday","year":"2000","journal-title":"Annu. Rev. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.clim.2004.05.003","article-title":"Distinct subpopulations of gamma delta T cells are present in normal and tumor-bearing human liver","volume":"113","author":"Kenna","year":"2004","journal-title":"Clin. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1002\/hep.22034","article-title":"Liver: An organ with predominant innate immunity","volume":"47","author":"Gao","year":"2008","journal-title":"Hepatology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1002\/hep.30952","article-title":"gammadelta T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming","volume":"71","author":"Wang","year":"2020","journal-title":"Hepatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.bpg.2017.09.008","article-title":"NAFLD, Helicobacter species and the intestinal microbiome","volume":"31","author":"Mitchell","year":"2017","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3389\/fimmu.2015.00015","article-title":"Five Layers of Receptor Signaling in gammadelta T-Cell Differentiation and Activation","volume":"6","author":"Ribeiro","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.4049\/jimmunol.1500375","article-title":"Adaptive Immune-like gamma\/delta T Lymphocytes Share Many Common Features with Their alpha\/beta T Cell Counterparts","volume":"195","author":"Lombes","year":"2015","journal-title":"J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"580968","DOI":"10.3389\/fimmu.2020.580968","article-title":"CD4(+) T Cells Mediate the Development of Liver Fibrosis in High Fat Diet-Induced NAFLD in Humanized Mice","volume":"11","author":"Her","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13839","DOI":"10.1038\/ncomms13839","article-title":"The microbiota maintain homeostasis of liver-resident gammadeltaT-17 cells in a lipid antigen\/CD1d-dependent manner","volume":"7","author":"Li","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1146\/annurev.immunol.16.1.201","article-title":"T cell memory","volume":"16","author":"Dutton","year":"1998","journal-title":"Annu. Rev. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.cyto.2014.09.011","article-title":"T cell subsets and their signature cytokines in autoimmune and inflammatory diseases","volume":"74","author":"Raphael","year":"2015","journal-title":"Cytokine"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1038\/nature01202","article-title":"Helper T cells regulate type-2 innate immunity in vivo","volume":"420","author":"Shinkai","year":"2002","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/nature16969","article-title":"NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis","volume":"531","author":"Ma","year":"2016","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4362","DOI":"10.4049\/jimmunol.1402384","article-title":"Regulatory T cells require TCR signaling for their suppressive function","volume":"194","author":"Schmidt","year":"2015","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1111\/imr.12029","article-title":"Metabolic control of the Treg\/Th17 axis","volume":"252","author":"Barbi","year":"2013","journal-title":"Immunol. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.3389\/fimmu.2018.02461","article-title":"Regulatory T Cells Suppress Effector T Cell Proliferation by Limiting Division Destiny","volume":"9","author":"Dowling","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"635","DOI":"10.3389\/fimmu.2018.00635","article-title":"The Contribution of Non-Professional Antigen-Presenting Cells to Immunity and Tolerance in the Liver","volume":"9","author":"Mehrfeld","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1007\/s10875-015-0160-6","article-title":"Oral Administration of OKT3 MAb to Patients with NASH, Promotes Regulatory T-cell Induction, and Alleviates Insulin Resistance: Results of a Phase IIa Blinded Placebo-Controlled Trial","volume":"35","author":"Lalazar","year":"2015","journal-title":"J. Clin. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Dywicki, J., Buitrago-Molina, L.E., Noyan, F., Davalos-Misslitz, A.C., Hupa-Breier, K.L., Lieber, M., Hapke, M., Schlue, J., Falk, C.S., and Raha, S. (2021). The Detrimental Role of Regulatory T Cells in Nonalcoholic Steatohepatitis. Hepatol. Commun.","DOI":"10.1002\/hep4.1807"},{"key":"ref_45","first-page":"1011","article-title":"Lack of fibroblast growth factor 21 accelerates metabolic liver injury characterized by steatohepatities in mice","volume":"6","author":"Liu","year":"2016","journal-title":"Am. J. Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/nrgastro.2012.79","article-title":"Increased risk of cardiovascular disease and chronic kidney disease in NAFLD","volume":"9","author":"Bonora","year":"2012","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/hep4.1041","article-title":"Hepatic Natural Killer T-cell and CD8+ T-cell Signatures in Mice with Nonalcoholic Steatohepatitis","volume":"1","author":"Bhattacharjee","year":"2017","journal-title":"Hepatol. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"G211","DOI":"10.1152\/ajpgi.00040.2019","article-title":"CD8(+) T cells regulate liver injury in obesity-related nonalcoholic fatty liver disease","volume":"318","author":"Breuer","year":"2020","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4474","DOI":"10.1038\/s41467-021-24734-0","article-title":"CD8(+) tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells","volume":"12","author":"Koda","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"8490","DOI":"10.1096\/fj.201802534RR","article-title":"The immunoregulatory effects of CD8 T-cell-derived perforin on diet-induced nonalcoholic steatohepatitis","volume":"33","author":"Wang","year":"2019","journal-title":"FASEB J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.immuni.2006.11.011","article-title":"Ito cells are liver-resident antigen-presenting cells for activating T cell responses","volume":"26","author":"Winau","year":"2007","journal-title":"Immunity"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1002\/hep.27632","article-title":"Inhibition of type I natural killer T cells by retinoids or following sulfatide-mediated activation of type II natural killer T cells attenuates alcoholic liver disease in mice","volume":"61","author":"Maricic","year":"2015","journal-title":"Hepatology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.3389\/fimmu.2018.01994","article-title":"Mucosal-Associated Invariant T Cells Improve Nonalcoholic Fatty Liver Disease Through Regulating Macrophage Polarization","volume":"9","author":"Li","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1038\/s41467-018-04450-y","article-title":"Mucosal-associated invariant T cells are a profibrogenic immune cell population in the liver","volume":"9","author":"Hegde","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/hep.26494","article-title":"Microbiota-liver axis in hepatic disease","volume":"59","author":"Chassaing","year":"2014","journal-title":"Hepatology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.it.2014.09.003","article-title":"gammadelta T cell surveillance via CD1 molecules","volume":"35","author":"Luoma","year":"2014","journal-title":"Trends Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"571847","DOI":"10.3389\/fmicb.2020.571847","article-title":"Gut Microbiome Contributes to Liver Fibrosis Impact on T Cell Receptor Immune Repertoire","volume":"11","author":"Liang","year":"2020","journal-title":"Front. Microbiol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Gebru, Y.A., Choi, M.R., Raja, G., Gupta, H., Sharma, S.P., Choi, Y.R., Kim, H.S., Yoon, S.J., Kim, D.J., and Suk, K.T. (2021). Pathophysiological Roles of Mucosal-Associated Invariant T Cells in the Context of Gut Microbiota-Liver Axis. Microorganisms, 9.","DOI":"10.3390\/microorganisms9020296"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.3389\/fimmu.2018.02082","article-title":"Complex Network of NKT Cell Subsets Controls Immune Homeostasis in Liver and Gut","volume":"9","author":"Marrero","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/nri3365","article-title":"Innate lymphoid cells\u2014A proposal for uniform nomenclature","volume":"13","author":"Spits","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1002\/eji.201646559","article-title":"Tissue-resident Eomes(hi) T-bet(lo) CD56(bright) NK cells with reduced proinflammatory potential are enriched in the adult human liver","volume":"46","author":"Harmon","year":"2016","journal-title":"Eur. J. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1159\/000365632","article-title":"Human natural killer cells: Origin, receptors, function, and clinical applications","volume":"164","author":"Moretta","year":"2014","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/S0168-8278(98)80206-7","article-title":"Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes","volume":"28","author":"Norris","year":"1998","journal-title":"J. Hepatol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Perales, M.-A., Abutalib, S.A., and Bollard, C. (2019). Natural Killer Cells: What Have We Learned?. Cell and Gene Therapies, Springer International Publishing.","DOI":"10.1007\/978-3-319-54368-0"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/S1471-4906(01)02060-9","article-title":"The biology of human natural killer-cell subsets","volume":"22","author":"Cooper","year":"2001","journal-title":"Trends Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"293","DOI":"10.3389\/fimmu.2017.00293","article-title":"Role of Distinct Natural Killer Cell Subsets in Anticancer Response","volume":"8","author":"Stabile","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1002\/eji.1830261032","article-title":"CD94 functions as a natural killer cell inhibitory receptor for different HLA class I alleles: Identification of the inhibitory form of CD94 by the use of novel monoclonal antibodies","volume":"26","author":"Sivori","year":"1996","journal-title":"Eur. J. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/sj.emboj.7600019","article-title":"Unravelling natural killer cell function: Triggering and inhibitory human NK receptors","volume":"23","author":"Moretta","year":"2004","journal-title":"EMBO J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/ni0508-477","article-title":"Natural killer cell recognition of missing self","volume":"9","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.3389\/fimmu.2019.01812","article-title":"On the Way to Become a Natural Killer Cell","volume":"10","author":"Mikulak","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/nri911","article-title":"Functional significance of the perforin\/granzyme cell death pathway","volume":"2","author":"Trapani","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3599","DOI":"10.1182\/blood-2012-04-425397","article-title":"NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17)","volume":"121","author":"Romee","year":"2013","journal-title":"Blood"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3739","DOI":"10.4049\/jimmunol.180.6.3739","article-title":"CD27 Defines Phenotypically and Functionally Different Human NK Cell Subsets","volume":"180","author":"Vossen","year":"2008","journal-title":"J. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1586\/17474124.1.1.173","article-title":"Activation of natural killer cells inhibits liver fibrosis: A novel strategy to treat liver fibrosis","volume":"1","author":"Gao","year":"2007","journal-title":"Expert. Rev. Gastroenterol. Hepatol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1172\/JCI66381","article-title":"Liver-resident NK cells confer adaptive immunity in skin-contact inflammation","volume":"123","author":"Peng","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_76","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_77","doi-asserted-by":"crossref","first-page":"e01659","DOI":"10.7554\/eLife.01659","article-title":"Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells","volume":"3","author":"Sojka","year":"2014","journal-title":"eLife"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1189\/jlb.72.4.668","article-title":"Hepatic natural killer cells exclusively kill splenic\/blood natural killer-resistant tumor cells by the perforin\/granzyme pathway","volume":"72","author":"Vermijlen","year":"2002","journal-title":"J. Leukoc. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.cellsig.2017.02.006","article-title":"Hepatic stellate cell interferes with NK cell regulation of fibrogenesis via curcumin induced senescence of hepatic stellate cell","volume":"33","author":"Jin","year":"2017","journal-title":"Cell. Signal."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1038\/cmi.2017.72","article-title":"Liver-resident NK cells and their potential functions","volume":"14","author":"Peng","year":"2017","journal-title":"Cell. Mol. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1053\/j.gastro.2005.10.055","article-title":"Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners","volume":"130","author":"Radaeva","year":"2006","journal-title":"Gastroenterology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1136\/gutjnl-2011-301400","article-title":"NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis","volume":"61","author":"Gur","year":"2012","journal-title":"Gut"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1002\/JLB.2A0118-031RR","article-title":"Activated NK cells kill hepatic stellate cells via p38\/PI3K signaling in a TRAIL-involved degranulation manner","volume":"105","author":"Li","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1002\/hep.26115","article-title":"Natural killer cells in liver disease","volume":"57","author":"Tian","year":"2013","journal-title":"Hepatology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1002\/hep.23253","article-title":"Major histocompatibility complex class I-related chains A and B (MIC A\/B): A novel role in nonalcoholic steatohepatitis","volume":"51","author":"Kahraman","year":"2010","journal-title":"Hepatology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1038\/s41590-018-0251-7","article-title":"Metabolic reprogramming of natural killer cells in obesity limits antitumor responses","volume":"19","author":"Michelet","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.3389\/fimmu.2019.02180","article-title":"The Obese Liver Environment Mediates Conversion of NK Cells to a Less Cytotoxic ILC1-Like Phenotype","volume":"10","author":"Cuff","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.clim.2016.01.007","article-title":"Alteration of Natural Killer cell phenotype and function in obese individuals","volume":"177","author":"Viel","year":"2017","journal-title":"Clin. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1002\/hep.28389","article-title":"NKp46(+) natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice","volume":"63","author":"Krueger","year":"2016","journal-title":"Hepatology"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Diedrich, T., Kummer, S., Galante, A., Drolz, A., Schlicker, V., Lohse, A.W., Kluwe, J., Eberhard, J.M., and Schulze Zur Wiesch, J. (2020). Characterization of the immune cell landscape of patients with NAFLD. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0230307"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.3389\/fimmu.2019.01255","article-title":"Retained NK Cell Phenotype and Functionality in Non-alcoholic Fatty Liver Disease","volume":"10","author":"Stiglund","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.immuni.2017.01.008","article-title":"Adipose Type One Innate Lymphoid Cells Regulate Macrophage Homeostasis through Targeted Cytotoxicity","volume":"46","author":"Boulenouar","year":"2017","journal-title":"Immunity"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.cmet.2016.03.002","article-title":"Adipose Natural Killer Cells Regulate Adipose Tissue Macrophages to Promote Insulin Resistance in Obesity","volume":"23","author":"Lee","year":"2016","journal-title":"Cell Metab."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/hep4.1146","article-title":"Insulin signaling as a potential natural killer cell checkpoint in fatty liver disease","volume":"2","author":"Amer","year":"2018","journal-title":"Hepatol. Commun."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/978-1-60761-362-6_32","article-title":"Isolation of NK cells and NK-like cells from the intestinal lamina propria","volume":"612","author":"Sanos","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1007\/s11427-017-9128-3","article-title":"Gut-liver axis: Gut microbiota in shaping hepatic innate immunity","volume":"60","author":"Wu","year":"2017","journal-title":"Sci. China Life Sci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0008-8749(83)90257-5","article-title":"Natural killing and antibody-dependent cellular cytotoxicity: Characterization of effector cells by E-rosetting and monoclonal antibodies","volume":"78","author":"Froelich","year":"1983","journal-title":"Cell. Immunol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/ijc.2910160204","article-title":"Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity","volume":"16","author":"Herberman","year":"1975","journal-title":"Int. J. Cancer"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.immuni.2012.05.020","article-title":"Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota","volume":"37","author":"Ganal","year":"2012","journal-title":"Immunity"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.7150\/ijbs.46405","article-title":"The Gut-liver Axis in Immune Remodeling: New insight into Liver Diseases","volume":"16","author":"Yang","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.immuni.2014.05.015","article-title":"Finding the missing links among metabolites, microbes, and the host","volume":"40","author":"Dorrestein","year":"2014","journal-title":"Immunity"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1126\/science.1223813","article-title":"Host-gut microbiota metabolic interactions","volume":"336","author":"Nicholson","year":"2012","journal-title":"Science"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"3294","DOI":"10.1038\/s41467-018-05470-4","article-title":"Microbial tryptophan catabolites in health and disease","volume":"9","author":"Roager","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"572","DOI":"10.4049\/jimmunol.1601247","article-title":"Microbiome-Modulated Metabolites at the Interface of Host Immunity","volume":"198","author":"Blacher","year":"2017","journal-title":"J. Immunol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"16014","DOI":"10.1038\/npjbiofilms.2016.14","article-title":"Bidirectional communication between the Aryl hydrocarbon Receptor (AhR) and the microbiome tunes host metabolism","volume":"2","author":"Korecka","year":"2016","journal-title":"NPJ Biofilms Microbiomes"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/s40495-019-00197-2","article-title":"Activation of the Ah Receptor Modulates Gastrointestinal Homeostasis and the Intestinal Microbiome","volume":"5","author":"Muku","year":"2019","journal-title":"Curr. Pharmacol. Rep."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/j.celrep.2018.03.109","article-title":"Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages","volume":"23","author":"Krishnan","year":"2018","journal-title":"Cell Rep."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e00985-20","DOI":"10.1128\/mSystems.00985-20","article-title":"Impaired Intestinal Akkermansia muciniphila and Aryl Hydrocarbon Receptor Ligands Contribute to Nonalcoholic Fatty Liver Disease in Mice","volume":"6","author":"Shi","year":"2021","journal-title":"mSystems"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1124\/pr.114.009001","article-title":"The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology","volume":"67","author":"Esser","year":"2015","journal-title":"Pharmacol. Rev."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.immuni.2011.11.011","article-title":"The Aryl Hydrocarbon Receptor Regulates Gut Immunity through Modulation of Innate Lymphoid Cells","volume":"36","author":"Qiu","year":"2012","journal-title":"Immunity"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.immuni.2017.12.012","article-title":"Regulation of the Immune Response by the Aryl Hydrocarbon Receptor","volume":"48","author":"Quintana","year":"2018","journal-title":"Immunity"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1038\/nrc3846","article-title":"Aryl hydrocarbon receptor ligands in cancer: Friend and foe","volume":"14","author":"Murray","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1084\/jem.20151998","article-title":"The aryl hydrocarbon receptor is required for the maintenance of liver-resident natural killer cells","volume":"213","author":"Zhang","year":"2016","journal-title":"J. Exp. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12190\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:28:24Z","timestamp":1760167704000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12190"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,11]]},"references-count":113,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222212190"],"URL":"https:\/\/doi.org\/10.3390\/ijms222212190","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,11]]}}}