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01-08-2021 | Autoimmune Hepatitis | Review

Functional heterogeneity of CD4⁺ T cells in liver inflammation

Authors: Franziska Muscate, Anna Woestemeier, Nicola Gagliani

Published in: Seminars in Immunopathology | Issue 4/2021

Abstract

CD4⁺ T cells play an essential role in orchestrating adequate immunity, but their overactivity has been associated with the development of immune-mediated inflammatory diseases, including liver inflammatory diseases. These cells can be subclassified according to their maturation stage, cytokine profile, and pro or anti-inflammatory functions, i.e., functional heterogeneity. In this review, we summarize what has been discovered so far regarding the role of the different CD4⁺ T cell polarization states in the progression of two prominent and still different liver inflammatory diseases: non-alcoholic steatohepatitis (NASH) and autoimmune hepatitis (AIH). Finally, the potential of CD4⁺ T cells as a therapeutic target in both NASH and AIH is discussed.

Anstee QM, Reeves HL, Kotsiliti E, Govaere O, & Heikenwalder M (2019) From NASH to HCC: current concepts and future challenges. In Nature Reviews Gastroenterology and Hepatology (Vol. 16, Issue 7, pp. 411–428). Nature Publishing Group. https://doi.org/10.1038/s41575-019-0145-7

Asrani SK, Devarbhavi H, Eaton J, & Kamath PS (2019) Burden of liver diseases in the world. In Journal of Hepatology (Vol. 70, Issue 1, pp. 151–171). Elsevier B.V. https://doi.org/10.1016/j.jhep.2018.09.014

Baaten BJG, Cooper AM, Swain SL, & Bradley LM (2013) Location, location, location: the impact of migratory heterogeneity on T cell function. In Frontiers in Immunology (Vol. 4, Issue OCT). Front Immunol. https://doi.org/10.3389/fimmu.2013.00311

Bäckhed F, Ding H, Wang T, Hooper LV, Gou YK, Nagy A, Semenkovich CF, Gordon JI (2004) The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 101(44):15718–15723. https://doi.org/10.1073/pnas.0407076101CrossRefPubMedPubMedCentral

Balitzer D, Shafizadeh N, Peters MG, Ferrell LD, Alshak N, Kakar S (2017) Autoimmune hepatitis: review of histologic features included in the simplified criteria proposed by the international autoimmune hepatitis group and proposal for new histologic criteria. Mod Pathol 30(5):773–783. https://doi.org/10.1038/modpathol.2016.267CrossRefPubMed

Behfarjam F, Nasseri-Moghaddam S, Jadali Z (2019) Enhanced Th17 responses in patients with autoimmune hepatitis. Middle East J Digest Dis 11(2):98–103. https://doi.org/10.15171/mejdd.2018.134CrossRef

Bertola A, Bonnafous S, Anty R, Patouraux S, Saint-Paul MC, Iannelli A, Gugenheim J, Barr J, Mato JM, Le Marchand-Brustel Y, Tran A, & Gual P (2010) Hepatic expression patterns of inflammatory and immune response genes associated with obesity and nash in morbidly obese patients. PLoS ONE 5(10). https://doi.org/10.1371/journal.pone.0013577

Bertolino P, McCaughan GW, & Bowen DG (2002) Role of primary intrahepatic T-cell activation in the “liver tolerance effect.” In Immunology and Cell Biology (Vol. 80, Issue 1, pp. 84–92). Immunol Cell Biol. https://doi.org/10.1046/j.0818-9641.2001.01048.x

Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, Herold KC, Lares A, Lee MR, Li K, Liu W, Long SA, Masiello LM, Nguyen V, Putnam AL, Rieck M, Sayre PH, & Tang Q (2015) Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med 7(315). https://doi.org/10.1126/scitranslmed.aad4134

10.

Boujedidi H, Robert O, Bignon A, Cassard-Doulcier AM, Renoud ML, Gary-Gouy H, Hemon P, Tharinger H, Prévot S, Bachelerie F, Naveau S, Emilie D, Balabanian K, Perlemuter G (2015) CXCR4 dysfunction in non-alcoholic steatohepatitis in mice and patients. Clin Sci 128(4):257–267. https://doi.org/10.1042/CS20130833CrossRef

11.

Boursier J, Mueller O, Barret M, Machado M, Fizanne L, Araujo-Perez F, Guy CD, Seed PC, Rawls JF, David LA, Hunault G, Oberti F, Calès P, Diehl AM (2016) The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63(3):764–775. https://doi.org/10.1002/hep.28356CrossRefPubMed

12.

Bovensiepen CS, Schakat M, Sebode M, Zenouzi R, Hartl J, Peiseler M, Li J, Henze L, Woestemeier A, Schramm C, Lohse AW, Herkel J, Weiler-Normann C (2019) TNF-producing Th1 cells are selectively expanded in liver infiltrates of patients with autoimmune hepatitis. J Immunol 203(12):3148–3156. https://doi.org/10.4049/jimmunol.1900124CrossRefPubMed

13.

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424. https://doi.org/10.3322/caac.21492CrossRef

14.

Breous E, Somanathan S, Vandenberghe LH, Wilson JM (2009) Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver. Hepatology 50(2):612–621. https://doi.org/10.1002/hep.23043CrossRefPubMed

15.

Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, DeFor T, Levine BL, June CH, Rubinstein P, McGlave PB, Blazar BR, Wagner JE (2011) Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: Safety profile and detection kinetics. Blood 117(3):1061–1070. https://doi.org/10.1182/blood-2010-07-293795CrossRefPubMedPubMedCentral

16.

Buitrago-Molina LE, Pietrek J, Noyan F, Schlue J, Manns MP, Wedemeyer H, Hardtke-Wolenski M, Jaeckel E (2021) Treg-specific IL-2 therapy can reestablish intrahepatic immune regulation in autoimmune hepatitis. J Autoimmun 117:102591. https://doi.org/10.1016/j.jaut.2020.102591CrossRefPubMed

17.

Burghardt S, Claass B, Erhardt A, Karimi K, Tiegs G (2014) Hepatocytes induce Foxp3 + regulatory T cells by notch signaling. J Leukoc Biol 96(4):571–577. https://doi.org/10.1189/jlb.2ab0613-342rrCrossRefPubMed

18.

Butcher EC, Williams M, Youngman K, Rott L, Briskin M (1999) Lymphocyte trafficking and regional immunity. Adv Immunol 72(72):209–253. https://doi.org/10.1016/s0065-2776(08)60022-xCrossRefPubMed

19.

Carambia A, Freund B, Schwinge D, Heine M, Laschtowitz A, Huber S, Wraith DC, Korn T, Schramm C, Lohse AW, Heeren J, Herkel J (2014) TGF-β-dependent induction of CD4+CD25+Foxp3 + Tregs by liver sinusoidal endothelial cells. J Hepatol 61(3):594–599. https://doi.org/10.1016/j.jhep.2014.04.027CrossRefPubMed

20.

Chen YY, Jeffery HC, Hunter S, Bhogal R, Birtwistle J, Braitch MK, Roberts S, Ming M, Hannah J, Thomas C, Adali G, Hübscher SG, Syn WK, Afford S, Lalor PF, Adams DH, Oo YH (2016) Human intrahepatic regulatory T cells are functional, require IL-2 from effector cells for survival, and are susceptible to Fas ligand-mediated apoptosis. Hepatology 64(1):138–150. https://doi.org/10.1002/hep.28517CrossRefPubMed

21.

Cherñavsky AC, Paladino N, Rubio AE, De Biasio MB, Periolo N, Cuarterolo M, Goñi J, Galoppo C, Cañero-Velasco MC, Muñoz AE, Fainboim H, Fainboim L (2004) Simultaneous expression of Th1 cytokines and IL-4 confers severe characteristics to type I autoimmune hepatitis in children. Hum Immunol 65(7):683–691. https://doi.org/10.1016/j.humimm.2004.03.004CrossRefPubMed

22.

Crispe IN (2011) Liver antigen-presenting cells. In Journal of Hepatology (Vol. 54, Issue 2, pp. 357–365). J Hepatol. https://doi.org/10.1016/j.jhep.2010.10.005

23.

Cyster JG (2005) Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. In Annual Review of Immunology (Vol. 23, pp. 127–159). Annu Rev Immunol. https://doi.org/10.1146/annurev.immunol.23.021704.115628

24.

Czaja AJ, Carpenter HA, Santrach PJ, Moore SB (1993) Significance of HLA DR4 in type 1 autoimmune hepatitis. Gastroenterology 105(5):1502–1507. https://doi.org/10.1016/0016-5085(93)90157-8CrossRefPubMed

25.

Derkow K, Loddenkemper C, Mintern J, Kruse N, Klugewitz K, Berg T, Wiedenmann B, Ploegh HL, Schott E (2007) Differential priming of CD8 and CD4 T-cells in animal models of autoimmune hepatitis and cholangitis. Hepatology 46(4):1155–1165. https://doi.org/10.1002/hep.21796CrossRefPubMed

26.

Doherty DG, Donaldson PT, Underhill JA, Farrant JM, Duthie A, Mieli-Vergani G, McFarlane IG, Johnson PJ, Eddleston ALWF, Mowat AP, Williams R (1994) Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis. Hepatology 19(3):609–615. https://doi.org/10.1002/hep.1840190311CrossRefPubMed

27.

Dunham RM, Thapa M, Velazquez VM, Elrod EJ, Denning TL, Pulendran B, Grakoui A (2013) Hepatic stellate cells preferentially induce Foxp3 + regulatory t cells by production of retinoic acid. J Immunol 190(5):2009–2016. https://doi.org/10.4049/jimmunol.1201937CrossRefPubMedPubMedCentral

28.

Fabre T, Kared H, Friedman SL, Shoukry NH (2014) IL-17A Enhances the expression of profibrotic genes through upregulation of the TGF-β receptor on hepatic stellate cells in a JNK-dependent manner. J Immunol 193(8):3925–3933. https://doi.org/10.4049/jimmunol.1400861CrossRefPubMed

29.

Fantuzzi L, Tagliamonte M, Gauzzi MC, & Lopalco L (2019) Dual CCR5/CCR2 targeting: opportunities for the cure of complex disorders. In Cellular and Molecular Life Sciences (Vol. 76, Issue 24, pp. 4869–4886). Springer. https://doi.org/10.1007/s00018-019-03255-6

30.

Farhadi A, Gundlapalli S, Shaikh M, Frantzides C, Harrell L, Kwasny MM, Keshavarzian A (2008) Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis. Liver Int 28(7):1026–1033. https://doi.org/10.1111/j.1478-3231.2008.01723.xCrossRefPubMedPubMedCentral

31.

Ferreyra Solari NE, Inzaugarat ME, Baz P, De Matteo E, Lezama C, Galoppo M, Galoppo C, Cherñavsky AC (2012) The role of innate cells is coupled to a Th1-polarized immune response in pediatric nonalcoholic steatohepatitis. J Clin Immunol 32(3):611–621. https://doi.org/10.1007/s10875-011-9635-2CrossRefPubMed

32.

Fragoulis GE, Siebert S, Mcinnes IB (2016) Therapeutic targeting of IL-17 and IL-23 cytokines in immune-mediated diseases. Annu Rev Med 67:337–353. https://doi.org/10.1146/annurev-med-051914-021944CrossRefPubMed

33.

French JB, Bonacini M, Ghabril M, Foureau D, & Bonkovsky HL (2016) Hepatotoxicity associated with the use of anti-TNF-α agents. In Drug Safety (Vol. 39, Issue 3, pp. 199–208). Springer International Publishing. https://doi.org/10.1007/s40264-015-0366-9

34.

Gagliani N, Amezcua Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, De Zoete MR, Licona-Limón P, Paiva RS, Ching T, Weaver C, Zi X, Pan X, Fan R, Garmire LX, Cotton MJ, Drier Y, Bernstein B, Geginat J, … Flavell RA (2015) TH17 cells transdifferentiate into regulatory T cells uring resolution of inflammation. Nature 523(7559):221–225. https://doi.org/10.1038/nature14452

35.

Giles DA, Moreno-Fernandez ME, Stankiewicz TE, Cappelletti M, Huppert SS, Iwakura Y, Dong C, Shanmukhappa SK, & Divanovic S (2016) Regulation of inflammation by IL-17A and IL-17F modulates non-alcoholic fatty liver disease pathogenesis. PLoS ONE 11(2). https://doi.org/10.1371/journal.pone.0149783

36.

Gomes AL, Teijeiro A, Burén S, Tummala KS, Yilmaz M, Waisman A, Theurillat JP, Perna C, Djouder N (2016) Metabolic Inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell 30(1):161–175. https://doi.org/10.1016/j.ccell.2016.05.020CrossRefPubMed

37.

Grant CR, Liberal R, Holder BS, Cardone J, Ma Y, Robson SC, Mieli-Vergani G, Vergani D, Longhi MS (2014) Dysfunctional CD39POS regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis. Hepatology 59(3):1007–1015. https://doi.org/10.1002/hep.26583CrossRefPubMed

38.

Haas JT, Vonghia L, Mogilenko DA, Verrijken A, Molendi-Coste O, Fleury S, Deprince A, Nikitin A, Woitrain E, Ducrocq-Geoffroy L, Pic S, Derudas B, Dehondt H, Gheeraert C, Van Gaal L, Driessen A, Lefebvre P, Staels B, Francque S, Dombrowicz D (2019) Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution. Nat Metab 1(6):604–614. https://doi.org/10.1038/s42255-019-0076-1CrossRefPubMedPubMedCentral

39.

Harbour SN, Maynard CL, Zindl CL, Schoeb TR, Weaver CT (2015) Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci USA 112(22):7061–7066. https://doi.org/10.1073/pnas.1415675112CrossRefPubMedPubMedCentral

40.

Hardtke-Wolenski M, Taubert R, Noyan F, Sievers M, Dywicki J, Schlue J, Falk CS, Ardesjö Lundgren B, Scott HS, Pich A, Anderson MS, Manns MP, Jaeckel E (2015) Autoimmune hepatitis in a murine autoimmune polyendocrine syndrome type 1 model is directed against multiple autoantigens. Hepatology 61(4):1295–1305. https://doi.org/10.1002/hep.27639CrossRefPubMed

41.

Harley ITW, Stankiewicz TE, Giles DA, Softic S, Flick LM, Cappelletti M, Sheridan R, Xanthakos SA, Steinbrecher KA, Sartor RB, Kohli R, Karp CL, Divanovic S (2014) IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice. Hepatology 59(5):1830–1839. https://doi.org/10.1002/hep.26746CrossRefPubMed

42.

Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA (2012) Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482(7384):179–185. https://doi.org/10.1038/nature10809CrossRefPubMedPubMedCentral

43.

Heneghan MA, Yeoman AD, Verma S, Smith AD, Longhi MS (2013) Autoimmune hepatitis. The Lancet 382(9902):1433–1444. https://doi.org/10.1016/S0140-6736(12)62163-1CrossRef

44.

Herck MAV, Weyler J, Kwanten WJ, Dirinck EL, Winter BYD, Francque SM, & Vonghia L (2019) The differential roles of T-cells in non-alcoholic fatty liver disease and obsity. In Frontiers in Immunology (Vol. 10, Issue FEB). Frontiers Media S.A. https://doi.org/10.3389/fimmu.2019.00082

45.

Herkel J, Jagemann B, Wiegard C, Garcia Lazaro JF, Lueth S, Kanzler S, Blessing M, Schmitt E, Lohse AW (2003) MHC class II-expressing hepatocytes function as antigen-presenting cells and activate specific CD4 T lymphocytes. Hepatology 37(5):1079–1085. https://doi.org/10.1053/jhep.2003.50191CrossRefPubMed

46.

Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, Ahlfors H, Wilhelm C, Tolaini M, Menzel U, Garefalaki A, Potocnik AJ, Stockinger B (2011) Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol 12(3):255–263. https://doi.org/10.1038/ni.1993CrossRefPubMedPubMedCentral

47.

Horst AK, Neumann K, Diehl L, & Tiegs G (2016) Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells. In Cellular and Molecular Immunology (Vol. 13, Issue 3, pp. 277–292). Chinese Soc Immunology. https://doi.org/10.1038/cmi.2015.112

48.

Huang H, Deng Z (2019) Adoptive transfer of regulatory T cells stimulated by allogeneic hepatic stellate cells mitigates liver injury in mice with concanavalin a-induced autoimmune hepatitis. Biochem Biophys Res Commun 512(1):14–21. https://doi.org/10.1016/j.bbrc.2019.02.147CrossRefPubMed

49.

Ibrahim SH, Hirsova P, Gores GJ (2018) Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation. Gut 67(5):963–972. https://doi.org/10.1136/gutjnl-2017-315691CrossRefPubMed

50.

Inzaugarat ME, Ferreyra Solari NE, Billordo LA, Abecasis R, Gadano AC, Cherñavsky AC (2011) Altered phenotype and functionality of circulating immune cells characterize adult patients with nonalcoholic steatohepatitis. J Clin Immunol 31(6):1120–1130. https://doi.org/10.1007/s10875-011-9571-1CrossRefPubMed

51.

Jaruga B, Hong F, Kim WH, Gao B (2004) IFN-γ/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1. Am J Physiol - Gastrointest Liver Physiol 287(5):50–55. https://doi.org/10.1152/ajpgi.00184.2004CrossRef

52.

Jaruga B, Hong F, Sun R, Radaeva S, Gao B (2003) Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: up-regulating eotaxins and IL-5 and recruiting leukocytes. J Immunol 171(6):3233–3244. https://doi.org/10.4049/jimmunol.171.6.3233CrossRefPubMed

53.

Jeffery HC, Jeffery LE, Lutz P, Corrigan M, Webb GJ, Hirschfield GM, Adams DH, Oo YH (2017) Low-dose interleukin-2 promotes STAT-5 phosphorylation, Treg survival and CTLA-4-dependent function in autoimmune liver diseases. Clin Exp Immunol 188(3):394–411. https://doi.org/10.1111/cei.12940CrossRefPubMedPubMedCentral

54.

Jiang G, Yang HR, Wang L, Wildey GM, Fung J, Qian S, Lu L (2008) Hepatic stellate cells preferentially expand allogeneic CD4+CD25+FoxP3+ regulatory T cells in an IL-2-dependent manner. Transplantation 86(11):1492–1502. https://doi.org/10.1097/TP.0b013e31818bfd13CrossRefPubMedPubMedCentral

55.

John K, Hardtke-Wolenski M, Jaeckel E, Manns MP, Schulze-Osthoff K, & Bantel H (2017) Increased apoptosis of regulatory T cells in patients with active autoimmune hepatitis. In Cell Death and Disease (Vol. 8, Issue 12, p. 3219). Nature Publishing Group. https://doi.org/10.1038/s41419-017-0010-y

56.

Karampetsou MP, Liossis SNC, & Sfikakis PP (2010) TNF-α antagonists beyond approved indications: stories of success and prospects for the future. In QJM (Vol. 103, Issue 12, pp. 917–928). QJM. https://doi.org/10.1093/qjmed/hcq152

57.

Karmaus PWF, Chen X, Lim SA, Herrada AA, Nguyen TLM, Xu B, Dhungana Y, Rankin S, Chen W, Rosencrance C, Yang K, Fan Y, Cheng Y, Easton J, Neale G, Vogel P, Chi H (2019) Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity. Nature 565(7737):101–105. https://doi.org/10.1038/s41586-018-0806-7CrossRefPubMed

58.

Katz SC, Pillarisetty VG, Bleier JI, Shah AB, DeMatteo RP (2004) Liver sinusoidal endothelial cells are insufficient to activate T cells. J Immunol 173(1):230–235. https://doi.org/10.4049/jimmunol.173.1.230CrossRefPubMed

59.

Kleinschmidt D, Giannou AD, McGee HM, Kempski J, Steglich B, Huber FJ, Ernst TM, Shiri AM, Wegscheid C, Tasika E, Hübener P, Huber P, Bedke T, Steffens N, Agalioti T, Fuchs T, Noll J, Lotter H, Tiegs G, … Huber S (2017) A protective function of Il-22BP in ischemia reperfusion and acetaminophen-induced liver injury. J Immunol 199(12):4078–4090. https://doi.org/10.4049/jimmunol.1700587

60.

Knolle PA, Schmitt E, Jin S, Germann T, Duchmann R, Hegenbarth S, Gerken G, Lohse AW (1999) Induction of cytokine production in naive CD4+ T cells by antigen- presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward T(h1) cells. Gastroenterology 116(6):1428–1440. https://doi.org/10.1016/S0016-5085(99)70508-1CrossRefPubMed

61.

Korniejewska A, Mcknight AJ, Johnson Z, Watson ML, Ward SG (2011) Expression and agonist responsiveness of CXCR3 variants in human T lymphocytes. Immunology 132(4):503–515. https://doi.org/10.1111/j.1365-2567.2010.03384.xCrossRefPubMedPubMedCentral

62.

Krebs CF, Reimers D, Zhao Y, Paust HJ, Bartsch P, Nuñez S, Rosemblatt MV, Hellmig M, Kilian C, Borchers A, Enk LUB, Zinke M, Becker M, Schmid J, Klinge S, Wong MN, Puelles VG, Schmidt C, Bertram T, … Mittrücker HW (2020) Pathogen-induced tissue-resident memory TH17 (TRM17) cells amplify autoimmune kidney disease. Sci Immunol 5(50). https://doi.org/10.1126/SCIIMMUNOL.ABA4163

63.

Lafdil F, Wang H, Park O, Zhang W, Moritoki Y, Yin S, Fu XY, Gershwin ME, Lian ZX, & Gao B (2009) Myeloid STAT3 inhibits T cell-mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production. Gastroenterology 137(6). https://doi.org/10.1053/j.gastro.2009.08.004

64.

Lafdil F, Miller AM, Ki SH, & Gao B (2010) Th17 cells and their associated cytokines in liver diseases. In Cellular and Molecular Immunology (Vol. 7, Issue 4, pp. 250–254). Cell Mol Immunol. https://doi.org/10.1038/cmi.2010.5

65.

Lapierre P, Béland K, Yang R, Alvarez F (2013) Adoptive transfer of ex vivo expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance. Hepatology 57(1):217–227. https://doi.org/10.1002/hep.26023CrossRefPubMed

66.

Ley K, Laudanna C, Cybulsky MI, & Nourshargh S (2007) Getting to the site of inflammation: the leukocyte adhesion cascade updated. In Nature Reviews Immunology (Vol. 7, Issue 9, pp. 678–689). Nat Rev Immunol. https://doi.org/10.1038/nri2156

67.

Li W, Kuhr CS, Zheng XX, Carper K, Thomson AW, Reyes JD, Perkins JD (2008) New insights into mechanisms of spontaneous liver transplant tolerance: the role of Foxp3-expressing CD25+CD4+ regulatory T cells. Am J Transplant 8(8):1639–1651. https://doi.org/10.1111/j.1600-6143.2008.02300.xCrossRefPubMed

68.

Li M, Zhao W, Wang Y, Jin L, Jin G, Sun X, Wang W, Wang K, Xu X, Hao J, Jin R, Fu W, Sun Y, Chang Y, Huang X, Zhou X, Wu H, Zhang K, Ge Q (2020) A wave of Foxp3+ regulatory T cell accumulation in the neonatal liver plays unique roles in maintaining self-tolerance. Cell Mol Immunol 17(5):507–518. https://doi.org/10.1038/s41423-019-0246-9CrossRefPubMed

69.

Liang M, Liwen Z, Yun Z, Yanbo D, & Jianping C (2018) The imbalance between Foxp3+Tregs and Th1/Th17/Th22 cells in patients with newly diagnosed autoimmune hepatitis. J Immunol Res 2018. https://doi.org/10.1155/2018/3753081

70.

Liberal R, Grant C, Mieli-Vergani G, Vergani D, Longhi M (2012) PWE-281 Different effector T cell responses may account for different patterns of liver injury in childhood autoimmune liver disease. Gut 61(Suppl 2):A412.1-A412. https://doi.org/10.1136/gutjnl-2012-302514d.281CrossRef

71.

Liberal, Rodrigo, Krawitt, E. L., Vierling, J. M., Manns, M. P., Mieli-Vergani, G., & Vergani, D. (2016). Cutting edge issues in autoimmune hepatitis. In Journal of Autoimmunity (Vol. 75, pp. 6–19). Academic Press. https://doi.org/10.1016/j.jaut.2016.07.005

72.

Lim TY, Martinez-Llordella M, Kodela E, Gray E, Heneghan MA, Sanchez-Fueyo A (2018) Low-dose interleukin-2 for refractory autoimmune hepatitis. Hepatology 68(4):1649–1652. https://doi.org/10.1002/hep.30059CrossRefPubMed

73.

Liu Y, She W, Wang F, Li J, Wang J, Jiang W (2014) 3, 3′-diindolylmethane alleviates steatosis and the progression of NASH partly through shifting the imbalance of Treg/Th17 cells to Treg dominance. Int Immunopharmacol 23(2):489–498. https://doi.org/10.1016/j.intimp.2014.09.024CrossRefPubMed

74.

Lohr HF, Schlaak JF, Lohse AW, Bocher WO, Arenz M, Gerken G, Buschenfelde KM (1996) Autoreactive CD4+ LKM-specific and anticlonotypic T-cell responses in LKM-1 antibody-positive autoimmune hepatitis. Hepatology 24(6):1416–1421. https://doi.org/10.1002/hep.510240619CrossRefPubMed

75.

Lohse AW, Knolle PA, Bilo K, Uhrig A, Waldmann C, Ibe M, Schmitt E, Gerken G, Buschenfelde KHMZ (1996) Antigen-presenting function and B7 expression of murine sinusoidal endothelial cells and Kupffer cells. Gastroenterology 110(4):1175–1181. https://doi.org/10.1053/gast.1996.v110.pm8613007CrossRefPubMed

76.

Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D (2004) Impairment of CD4+CD25+ regulatory T-cells in autoimmune liver disease. J Hepatol 41(1):31–37. https://doi.org/10.1016/j.jhep.2004.03.008CrossRefPubMed

77.

Lu JG, Iyasu A, French B, Tillman B, French SW (2020) Overexpression of MHCII by hepatocytes in alcoholic hepatitis (AH) compared to non-alcoholic steatohepatitis (NASH) and normal controls. Alcohol 84:27–32. https://doi.org/10.1016/j.alcohol.2019.08.008CrossRefPubMed

78.

Lüth S, Huber S, Schramm C, Buch T, Zander S, Stadelmann C, Brück W, Wraith DC, Herkel J, Lohse AW (2008) Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. J Clin Investig 118(10):3403–3410. https://doi.org/10.1172/JCI32132CrossRefPubMedPubMedCentral

79.

Luther SA, & Cyster JG (2001) Chemokines as regulators of T cell differentiation. In Nature Immunology (Vol. 2, Issue 2, pp. 102–107). Nat Immunol. https://doi.org/10.1038/84205

80.

Ma X, Hua J, Mohamood AR, Hamad ARA, Ravi R, Li Z (2007) A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury. Hepatology 46(5):1519–1529. https://doi.org/10.1002/hep.21823CrossRefPubMed

81.

Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, Stroncek DF, Terabe M, Kapoor V, ElGindi M, Han M, Thornton AM, Zhang H, Egger M, Luo J, Felsher DW, McVicar DW, Weber A, Heikenwalder M, Greten TF (2016) NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531(7593):253–257. https://doi.org/10.1038/nature16969CrossRefPubMedPubMedCentral

82.

Manns MP, Lohse AW, & Vergani D (2015) Autoimmune hepatitis - update 2015. In Journal of Hepatology (Vol. 62, Issue S1, pp. S100–S111). Elsevier. https://doi.org/10.1016/j.jhep.2015.03.005

83.

Manousou P, Kolios G, Drygiannakis I, Koulentaki M, Pyrovolaki K, Voumvouraki A, Notas G, Bourikas L, Papadaki HA, Kouroumalis E (2013) CXCR3 axis in patients with primary biliary cirrhosis: a possible novel mechanism of the effect of ursodeoxycholic acid. Clin Exp Immunol 172(1):9–15. https://doi.org/10.1111/cei.12032CrossRefPubMedPubMedCentral

84.

Marek-Trzonkowska N, Wujtewicz MA, Myśliwiec M, Witkowski P, Dobyszuk A, Møynarski W, Grabowska M, Balcerska A, Techmańska I, Myśliwska J, Juścińska J, Trzonkowski P (2012) Administration of CD4 +CD25 highCD127 - regulatory T cells preserves β-cell function in type 1 diabetes in children. Diabetes Care 35(9):1817–1820. https://doi.org/10.2337/dc12-0038CrossRefPubMedPubMedCentral

85.

Matloubian M, & Cyster JG (2012) Th1 cell induction in lymph nodes according to a red-blue chemokine map. In Immunity (Vol. 37, Issue 6, pp. 954–956). Immunity. https://doi.org/10.1016/j.immuni.2012.11.007

86.

Mitra S, De A, & Chowdhury A (2020) Epidemiology of non-alcoholic and alcoholic fatty liver diseases. In Translational Gastroenterology and Hepatology (Vol. 5). AME Publishing Company. https://doi.org/10.21037/TGH.2019.09.08

87.

Mueller SN, Gebhardt T, Carbone FR, & Heath WR (2013) Memory T cell subsets, migration patterns, and tissue residence. In Annual Review of Immunology (Vol. 31, pp. 137–161). Annu Rev Immunol. https://doi.org/10.1146/annurev-immunol-032712-095954

88.

Nagata T, Mckinley L, Peschon JJ, Alcorn JF, Aujla SJ, Kolls JK (2008) Requirement of IL-17RA in Con A induced hepatitis and negative regulation of IL-17 production in mouse T cells. J Immunol 181(11):7473–7479. https://doi.org/10.4049/jimmunol.181.11.7473CrossRefPubMed

89.

Nishioji K, Okanoue T, Itoh Y, Narumi S, Sakamoto M, Nakamura H, Morita A, Kashima K (2001) Increase of chemokine interferon-inducible protein-10 (IP-10) in the serum of patients with autoimmune liver diseases and increase of its mRNA expression in hepatocytes. Clin Exp Immunol 123(2):271–279. https://doi.org/10.1046/j.1365-2249.2001.01391.xCrossRefPubMedPubMedCentral

90.

Oo YH & Sakaguchi S (2013) Regulatory T-cell directed therapies in liver diseases. In Journal of Hepatology (Vol. 59). https://doi.org/10.1016/j.jhep.2013.05.034

91.

Oo YH, Hubscher SG, & Adams DH (2010) Autoimmune hepatitis: New paradigms in the pathogenesis, diagnosis, and management. In Hepatology International (Vol. 4, Issue 2, pp. 475–493). Hepatol Int. https://doi.org/10.1007/s12072-010-9183-5

92.

Oo YH, Weston CJ, Lalor PF, Curbishley SM, Withers DR, Reynolds GM, Shetty S, Harki J, Shaw JC, Eksteen B, Hubscher SG, Walker LSK, Adams DH (2010) Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver. J Immunol 184(6):2886–2898. https://doi.org/10.4049/jimmunol.0901216CrossRefPubMed

93.

Oo YH, Ackrill S, Cole R, Jenkins L, Anderson P, Jeffery HC, Jones N, Jeffery LE, Lutz P, Wawman RE, Athwal AK, Thompson J, Gray J, Guo K, Barton D, Hirschfield GM, Wong T, Guest P, Adams DH (2019) Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis. JHEP Reports 1(4):286–296. https://doi.org/10.1016/j.jhepr.2019.08.001CrossRefPubMedPubMedCentral

94.

Peiseler M, Sebode M, Franke B, Wortmann F, Schwinge D, Quaas A, Baron U, Olek S, Wiegard C, Lohse AW, Weiler-Normann C, Schramm C, Herkel J (2012) FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency. J Hepatol 57(1):125–132. https://doi.org/10.1016/j.jhep.2012.02.029CrossRefPubMed

95.

Pellicoro A, Ramachandran P, Iredale JP, & Fallowfield JA (2014) Liver fibrosis and repair: immune regulation of wound healing in a solid organ. In Nature Reviews Immunology (Vol. 14, Issue 3, pp. 181–194). Nat Rev Immunol. https://doi.org/10.1038/nri3623

96.

Plaza-Sirvent C, Schuster M, Neumann Y, Heise U, Pils MC, Schulze-Osthoff K, Schmitz I (2017) c-FLIP Expression in Foxp3-expressing cells Is essential for survival of regulatory T cells and prevention of autoimmunity. Cell Rep 18(1):12–22. https://doi.org/10.1016/j.celrep.2016.12.022CrossRefPubMed

97.

Racanelli V, & Rehermann B (2006) The liver as an immunological organ. In Hepatology (Vol. 43, Issue 2 SUPPL. 1). Hepatology. https://doi.org/10.1002/hep.21060

98.

Radaeva S, Sun R, Pan HN, Hong F, Gao B (2004) Interleukin 22 (IL-22) Plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology 39(5):1332–1342. https://doi.org/10.1002/hep.20184CrossRefPubMed

99.

Rahman K, Desai C, Iyer SS, Thorn NE, Kumar P, Liu Y, Smith T, Neish AS, Li H, Tan S, Wu P, Liu X, Yu Y, Farris AB, Nusrat A, Parkos CA, Anania FA (2016) Loss of junctional adhesion molecule a promotes severe steatohepatitis in mice on a diet high in saturated fat, fructose, and cholesterol. Gastroenterology 151(4):733-746.e12. https://doi.org/10.1053/j.gastro.2016.06.022CrossRefPubMed

100.

Rai RP, Liu Y, Iyer SS, Liu S, Gupta B, Desai C, Kumar P, Smith T, Singhi AD, Nusrat A, Parkos CA, Monga SP, Czaja MJ, Anania FA, Raeman R (2020) Blocking integrin α4β7-mediated CD4 T cell recruitment to the intestine and liver protects mice from western diet-induced non-alcoholic steatohepatitis. J Hepatol 73(5):1013–1022. https://doi.org/10.1016/j.jhep.2020.05.047CrossRefPubMed

101.

Rau M, Schilling A-K, Meertens J, Hering I, Weiss J, Jurowich C, Kudlich T, Hermanns HM, Bantel H, Beyersdorf N, Geier A (2016) Progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis is marked by a higher frequency of Th17 cells in the liver and an increased Th17/resting regulatory T cell ratio in peripheral blood and in the liver. J Immunol 196(1):97–105. https://doi.org/10.4049/jimmunol.1501175CrossRefPubMed

102.

Reinhardt RL, Khoruts A, Merica R, Zell T, Jenkins MK (2001) Visualizing the generation of memory CD4 T cells in the whole body. Nature 410(6824):101–105. https://doi.org/10.1038/35065111CrossRefPubMed

103.

Renand A, Habes S, Mosnier J, Aublé H, Judor J, Vince N, Hulin P, Nedellec S, Métairie S, Archambeaud I, Brouard S, Gournay J, Conchon S (2018) Immune alterations in patients with type 1 autoimmune hepatitis persist upon standard immunosuppressive treatment. Hepatology Communications 2(8):972–985. https://doi.org/10.1002/hep4.1202CrossRef

104.

Rodrigues S, Lopes S, Magro F, Cardoso H, Horta e Vale AM, Marques M, Mariz E, Bernardes M, Lopes J, Carneiro F, Macedo G (2015) Autoimmune hepatitis and anti-tumor necrosis factor alpha therapy: a single center report of 8 cases. World J Gastroenterol 21(24):7584–7588. https://doi.org/10.3748/wjg.v21.i24.7584CrossRefPubMedPubMedCentral

105.

Roh YS, Kim JW, Park S, Shon C, Kim S, Eo SK, Kwon JK, Lim CW, Kim B (2018) Toll-like receptor-7 signaling promotes nonalcoholic steatohepatitis by inhibiting regulatory T cells in mice. Am J Pathol 188(11):2574–2588. https://doi.org/10.1016/j.ajpath.2018.07.011CrossRefPubMed

106.

Rolla S, Alchera E, Imarisio C, Bardina V, Valente G, Cappello P, Mombello C, Follenzi A, Novelli F, Carini R (2016) The balance between IL-17 and IL-22 produced by liver-infiltrating T-helper cells critically controls NASH development in mice. Clin Sci 130(3):193–203. https://doi.org/10.1042/CS20150405CrossRef

107.

Sánchez-Fueyo A, Whitehouse G, Grageda N, Cramp ME, Lim TY, Romano M, Thirkell S, Lowe K, Fry L, Heward J, Kerr A, Ali J, Fisher C, Lewis G, Hope A, Kodela E, Lyne M, Farzaneh F, Kordasti S, … Lombardi G (2020) Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation. Am J Transplant 20(4):1125–1136. https://doi.org/10.1111/ajt.15700

108.

Schlaak JF, Lohr H, Gallati H, Meyer-Zum-Buschenfelde KH, Fleischer B (1993) Analysis of the in vitro cytokine production by liver-infiltrating T cells of patients with autoimmune hepatitis. Clin Exp Immunol 94(1):168–173. https://doi.org/10.1111/j.1365-2249.1993.tb05996.xCrossRefPubMedPubMedCentral

109.

Schramm C, Lohse AW (2014) Autoimmune hepatitis on the rise. J Hepatol 60:478–479. https://doi.org/10.1016/j.jhep.2013.10.020CrossRefPubMed

110.

Shao X, Qian Y, Xu C, Hong B, Xu W, Shen L, Jin C, Wu Z, Tong X, & Yao H (2013) The protective effect of intrasplenic transplantation of Ad-IL-18BP/IL-4 gene-modified fetal hepatocytes on cona-induced hepatitis in mice. PLoS ONE 8(3). https://doi.org/10.1371/journal.pone.0058836

111.

Sun R, Park O, Horiguchi N, Kulkarni S, Jeong WI, Sun HY, Radaeva S, Gao B (2006) STAT1 contributes to dsRNA inhibition of liver regeneration after partial hepatectomy in mice. Hepatology 44(4):955–966. https://doi.org/10.1002/hep.21344CrossRefPubMed

112.

Sutti S, Jindal A, Locatelli I, Vacchiano M, Gigliotti L, Bozzola C, Albano E (2014) Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH. Hepatology 59(3):886–897. https://doi.org/10.1002/hep.26749CrossRefPubMed

113.

Takahashi A, Ohira H, Abe K, Zeniya M, Abe M, Arinaga-Hino T, Torimura T, Yoshizawa K, Takaki A, Kang JH, Suzuki Y, Nakamoto N, Inui A, Tanaka A, Takikawa H (2020) Increasing incidence of acute autoimmune hepatitis: a nationwide survey in Japan. Sci Rep 10(1):14250. https://doi.org/10.1038/s41598-020-71296-0CrossRefPubMedPubMedCentral

114.

Tan Z, Qian X, Jiang R, Liu Q, Wang Y, Chen C, Wang X, Ryffel B, Sun B (2013) IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation. J Immunol 191(4):1835–1844. https://doi.org/10.4049/jimmunol.1203013CrossRefPubMed

115.

Tang Y, Bian Z, Zhao L, Liu Y, Liang S, Wang Q, Han X, Peng Y, Chen X, Shen L, Qiu D, Li Z, Ma X (2011) Interleukin-17 exacerbates hepatic steatosis and inflammation in non-alcoholic fatty liver disease. Clin Exp Immunol 166(2):281–290. https://doi.org/10.1111/j.1365-2249.2011.04471.xCrossRefPubMedPubMedCentral

116.

Taubert R, Hardtke-Wolenski M, Noyan F, Wilms A, Baumann AK, Schlue J, Olek S, Falk CS, Manns MP, Jaeckel E (2014) Intrahepatic regulatory T cells in autoimmune hepatitis are associated with treatment response and depleted with current therapies. J Hepatol 61(5):1106–1114. https://doi.org/10.1016/j.jhep.2014.05.034CrossRefPubMed

117.

Taubert R, Hupa-Breier KL, Jaeckel E, & Manns MP (2018) Novel therapeutic targets in autoimmune hepatitis. In Journal of Autoimmunity (Vol. 95, pp. 34–46). Academic Press. https://doi.org/10.1016/j.jaut.2018.10.022

118.

Tay SS, Wong YC, Roediger B, Sierro F, Lu B, McDonald DM, McGuffog CM, Meyer NJ, Alexander IE, Parish IA, Heath WR, Weninger W, Bishop GA, Gamble JR, McCaughan GW, Bertolino P, Bowen DG (2014) Intrahepatic activation of naive CD4 + T cells by liver-resident phagocytic cells. J Immunol 193(5):2087–2095. https://doi.org/10.4049/jimmunol.1400037CrossRefPubMed

119.

Todo S, Yamashita K, Goto R, Zaitsu M, Nagatsu A, Oura T, Watanabe M, Aoyagi T, Suzuki T, Shimamura T, Kamiyama T, Sato N, Sugita J, Hatanaka K, Bashuda H, Habu S, Demetris AJ, Okumura K (2016) A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. Hepatology 64(2):632–643. https://doi.org/10.1002/hep.28459CrossRefPubMed

120.

Trzonkowski P, Bieniaszewska M, Juścińska J, Dobyszuk A, Krzystyniak A, Marek N, Myśliwska J, Hellmann A (2009) First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. Clin Immunol 133(1):22–26. https://doi.org/10.1016/j.clim.2009.06.001CrossRefPubMed

121.

Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444(7122):1027–1031. https://doi.org/10.1038/nature05414CrossRefPubMed

122.

Valean S, Acalovschi M, Dumitrascu DL, Ciobanu L, Nagy G, & Chira R (2019) Hepatocellular carcinoma in patients with autoimmune hepatitis – a systematic review of the literature published between 1989–2016. Med Pharm Rep 92(2). https://doi.org/10.15386/mpr-1228

123.

Vonghia L, Magrone T, Verrijken A, Michielsen P, Van Gaal L, Jirillo E, & Francque S (2015) Peripheral and hepatic vein cytokine levels in correlation with non-alcoholic fatty liver disease (NAFLD)-related metabolic, histological, and haemodynamic features. PLoS ONE 10(11). https://doi.org/10.1371/journal.pone.0143380

124.

Walker JA, & McKenzie ANJ (2018) TH2 cell development and function. In Nature Reviews Immunology (Vol. 18, Issue 2, pp. 121–133). Nature Publishing Group. https://doi.org/10.1038/nri.2017.118

125.

Webb GJ, Hirschfield GM, Krawitt EL, Gershwin ME (2018) Cellular and molecular mechanisms of autoimmune hepatitis. Annu Rev Pathol 13:247–292. https://doi.org/10.1146/annurev-pathol-020117-043534CrossRefPubMed

126.

Weiler-Normann C, Schramm C, Quaas A, Wiegard C, Glaubke C, Pannicke N, Möller S, Lohse AW (2013) Infliximab as a rescue treatment in difficult-to-treat autoimmune hepatitis. J Hepatol 58(3):529–534. https://doi.org/10.1016/j.jhep.2012.11.010CrossRefPubMed

127.

Wiegard C, Wolint P, Frenzel C, Cheruti U, Schmitt E, Oxenius A, Lohse AW, Herkel J (2007) Defective T helper response of hepatocyte-stimulated CD4 T cells impairs antiviral CD8 response and viral clearance. Gastroenterology 133(6):2010–2018. https://doi.org/10.1053/j.gastro.2007.09.007CrossRefPubMed

128.

Winau F, Hegasy G, Weiskirchen R, Weber S, Cassan C, Sieling PA, Modlin RL, Liblau RS, Gressner AM, Kaufmann SHE (2007) Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity 26(1):117–129. https://doi.org/10.1016/j.immuni.2006.11.011CrossRefPubMed

129.

Wong J, Johnston B, Lee SS, Bullard DC, Smith CW, Beaudet AL, Kubes P (1997) A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature. J Clin Investig 99(11):2782–2790. https://doi.org/10.1172/JCI119468CrossRefPubMedPubMedCentral

130.

Wuensch SA, Spahn J, Crispe IN (2010) Direct, help-independent priming of CD8+ T cells by adeno-associated virus-transduced hepatocytes. Hepatology 52(3):1068–1077. https://doi.org/10.1002/hep.23745CrossRefPubMed

131.

Xie G, Wang X, Liu P, Wei R, Chen W, Rajani C, Hernandez BY, Alegado R, Dong B, Li D, Jia W (2016) Distinctly altered gut microbiota in the progression of liver disease. Oncotarget 7(15):19355–19366. https://doi.org/10.18632/oncotarget.8466CrossRefPubMedPubMedCentral

132.

Xu H, Agalioti T, Zhao J, Steglich B, Wahib R, Vesely MCA, Bielecki P, Bailis W, Jackson R, Perez D, Izbicki J, Licona-Limón P, Kaartinen V, Geginat J, Esplugues E, Tolosa E, Huber S, Flavell RA, & Gagliani N (2020) The induction and function of the anti-inflammatory fate of TH17 cells. Nat Commun 11(1). https://doi.org/10.1038/s41467-020-17097-5

133.

Xu R, Tao A, Zhang S, Zhang M (2013) Neutralization of interleukin-17 attenuates high fat diet-induced non-alcoholic fatty liver disease in mice. Acta Biochim Biophys Sin 45(9):726–733. https://doi.org/10.1093/abbs/gmt065CrossRefPubMed

134.

Xu L, Yin W, Sun R, Wei H, Tian Z (2013) Liver type i regulatory T cells suppress germinal center formation in HBV-tolerant mice. Proc Natl Acad Sci USA 110(42):16993–16998. https://doi.org/10.1073/pnas.1306437110CrossRefPubMedPubMedCentral

135.

You Q, Cheng L, Kedl RM, Ju C (2008) Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology 48(3):978–990. https://doi.org/10.1002/hep.22395CrossRefPubMed

136.

Yu H, Huang J, Liu Y, Ai G, Yan W, Wang X, Ning Q (2010) IL-17 contributes to autoimmune hepatitis. Journal of Huazhong University of Science and Technology Medical Sciences = Hua Zhong Ke Ji Da Xue Xue Bao Yi Xue Ying De Wen Ban = Huazhong Keji Daxue Xuebao Yixue Yingdewen Ban 30(4):443–446. https://doi.org/10.1007/s11596-010-0446-0CrossRef

137.

Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Karow M, Flavell RA (2007) Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 27(4):647–659. https://doi.org/10.1016/j.immuni.2007.07.023CrossRefPubMedPubMedCentral

138.

Zhai M, Liu Z, Long J, Zhou Q, Yang L, Zhou Q, Liu S, Dai Y (2021) The incidence trends of liver cirrhosis caused by nonalcoholic steatohepatitis via the GBD study 2017. Sci Rep 11(1):5195. https://doi.org/10.1038/s41598-021-84577-zCrossRefPubMedPubMedCentral

139.

Zhao L, Tang Y, You Z, Wang Q, Liang S, Han X, Qiu D, Wei J, Liu Y, Shen L, Chen X, Peng Y, Li Z, & Ma X (2011) Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression. PLoS ONE 6(4). https://doi.org/10.1371/journal.pone.0018909

140.

Zhao Y, Zhang Y, Liu Y-M, Liu Y, Feng X, Liao H-Y, Vergani D, Ma Y, Yan H-P (2011) Identification of T cell epitopes on soluble liver antigen in Chinese patients with auto-immune hepatitis. Liver Int 31(5):721–729. https://doi.org/10.1111/j.1478-3231.2011.02487.xCrossRefPubMed

141.

Zheng C, Yin S, Yang Y, Yu Y, Xie X (2018) CD24 aggravates acute liver injury in autoimmune hepatitis by promoting IFN-γ 3 production by CD4+ T cells. Cell Mol Immunol 15(3):260–271. https://doi.org/10.1038/cmi.2016.57CrossRefPubMed

142.

Zocco MA, Carloni E, Pescatori M, Saulnier N, Lupascu A, Nista EC, Novi M, Candelli M, Cimica V, Mihm S, Gasbarrini G, Ramadori G, Gasbarrini A (2006) Characterization of gene expression profile in rat Kupffer cells stimulated with IFN-α or IFN-γ. Dig Liver Dis 38(8):563–577. https://doi.org/10.1016/j.dld.2006.04.015CrossRefPubMed

Title: Functional heterogeneity of CD4+ T cells in liver inflammation
Authors: Franziska Muscate
Anna Woestemeier
Nicola Gagliani
Publication date: 01-08-2021
Publisher: Springer Berlin Heidelberg
Keyword: Autoimmune Hepatitis
Published in: Seminars in Immunopathology / Issue 4/2021
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI: https://doi.org/10.1007/s00281-021-00881-w

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