1932

Abstract

The liver's unique characteristics have a profound impact on the priming and maintenance of adaptive immunity. This review delves into the cellular circuits that regulate adaptive immune responses in the liver, with a specific focus on hepatitis B virus infection as an illustrative example. A key aspect highlighted is the liver's specialized role in priming CD8+ T cells, leading to a distinct state of immune hyporesponsiveness. Additionally, the influence of the liver's hemodynamics and anatomical features, particularly during liver fibrosis and cirrhosis, on the differentiation and function of adaptive immune cells is discussed. While the primary emphasis is on CD8+ T cells, recent findings regarding the involvement of B cells and CD4+ T cells in hepatic immunity are also reviewed. Furthermore, we address the challenges ahead and propose integrating cutting-edge techniques, such as spatial biology, and combining mouse models with human sample analyses to gain comprehensive insights into the liver's adaptive immunity. This understanding could pave the way for novel therapeutic strategies targeting infectious diseases, malignancies, and inflammatory liver conditions like metabolic dysfunction-associated steatohepatitis and autoimmune hepatitis.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-090122-041354
2024-06-28
2024-07-05
Loading full text...

Full text loading...

/deliver/fulltext/immunol/42/1/annurev-immunol-090122-041354.html?itemId=/content/journals/10.1146/annurev-immunol-090122-041354&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Crispe IN. 2009.. The liver as a lymphoid organ. . Annu. Rev. Immunol. 27::14763
    [Crossref] [Google Scholar]
  2. 2.
    Ficht X, Iannacone M. 2020.. Immune surveillance of the liver by T cells. . Sci. Immunol. 5:(51):eaba2351
    [Crossref] [Google Scholar]
  3. 3.
    Calne RY, Sells RA, Pena JR, Davis DR, Millard PR, et al. 1969.. Induction of immunological tolerance by porcine liver allografts. . Nature 223:(5205):47276
    [Crossref] [Google Scholar]
  4. 4.
    Kamada N. 1985.. The immunology of experimental liver transplantation in the rat. . Immunology 55:(3):36989
    [Google Scholar]
  5. 5.
    Qian S, Demetris AJ, Murase N, Rao AS, Fung JJ, Starzl TE. 1994.. Murine liver allograft transplantation: tolerance and donor cell chimerism. . Hepatology 19:(4):91624
    [Crossref] [Google Scholar]
  6. 6.
    Benseler V, McCaughan G, Schlitt H, Bishop G, Bowen D, Bertolino P. 2007.. The liver: a special case in transplantation tolerance. . Semin. Liver Dis. 27:(2):194213
    [Crossref] [Google Scholar]
  7. 7.
    Mingozzi F, Liu Y-L, Dobrzynski E, Kaufhold A, Liu JH, et al. 2003.. Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. . J. Clin. Investig. 111:(9):134756
    [Crossref] [Google Scholar]
  8. 8.
    Akbarpour M, Goudy KS, Cantore A, Russo F, Sanvito F, et al. 2015.. Insulin B chain 9-23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3+ Tregs. . Sci. Transl. Med. 7:(289):289ra81
    [Crossref] [Google Scholar]
  9. 9.
    Guidotti LG, Chisari FV. 2006.. Immunobiology and pathogenesis of viral hepatitis. . Annu. Rev. Pathol. Mech. Dis. 1::2361
    [Crossref] [Google Scholar]
  10. 10.
    Iannacone M, Guidotti LG. 2022.. Immunobiology and pathogenesis of hepatitis B virus infection. . Nat. Rev. Immunol. 22:(1):1932
    [Crossref] [Google Scholar]
  11. 11.
    Sironi L, Bouzin M, Inverso D, D'Alfonso L, Pozzi P, et al. 2014.. In vivo flow mapping in complex vessel networks by single image correlation. . Sci. Rep. 4:(1):7341
    [Crossref] [Google Scholar]
  12. 12.
    Warren A, Couteur DGL, Fraser R, Bowen DG, McCaughan GW, Bertolino P. 2006.. T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. . Hepatology 44:(5):118290
    [Crossref] [Google Scholar]
  13. 13.
    Wisse E, de Zanger RB, Charels K, van der Smissen P, McCuskey RS. 1985.. The liver sieve: considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. . Hepatology 5:(4):68392
    [Crossref] [Google Scholar]
  14. 14.
    Ben-Moshe S, Itzkovitz S. 2019.. Spatial heterogeneity in the mammalian liver. . Nat. Rev. Gastroenterol. 16:(7):395410
    [Crossref] [Google Scholar]
  15. 15.
    Halpern KB, Shenhav R, Matcovitch-Natan O, Tóth B, Lemze D, et al. 2017.. Single-cell spatial reconstruction reveals global division of labour in the mammalian liver. . Nature 542:(7641):35256
    [Crossref] [Google Scholar]
  16. 16.
    Martini T, Naef F, Tchorz JS. 2023.. Spatiotemporal metabolic liver zonation and consequences on pathophysiology. . Annu. Rev. Pathol. Mech. Dis. 18::43966
    [Crossref] [Google Scholar]
  17. 17.
    Ben-Moshe S, Shapira Y, Moor AE, Manco R, Veg T, et al. 2019.. Spatial sorting enables comprehensive characterization of liver zonation. . Nat. Metab. 1:(9):899911
    [Crossref] [Google Scholar]
  18. 18.
    Droin C, Kholtei JE, Halpern KB, Hurni C, Rozenberg M, et al. 2021.. Space-time logic of liver gene expression at sub-lobular scale. . Nat. Metab. 3:(1):4358
    [Crossref] [Google Scholar]
  19. 19.
    Dobie R, Wilson-Kanamori JR, Henderson BEP, Smith JR, Matchett KP, et al. 2019.. Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis. . Cell Rep. 29:(7):183247.e8
    [Crossref] [Google Scholar]
  20. 20.
    Inverso D, Shi J, Lee KH, Jakab M, Ben-Moshe S, et al. 2021.. A spatial vascular transcriptomic, proteomic, and phosphoproteomic atlas unveils an angiocrine Tie-Wnt signaling axis in the liver. . Dev. Cell 56:(11):167793.e10
    [Crossref] [Google Scholar]
  21. 21.
    Guilliams M, Bonnardel J, Haest B, Vanderborght B, Wagner C, et al. 2022.. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. . Cell 185:(2):37996.e38
    [Crossref] [Google Scholar]
  22. 22.
    David BA, Rezende RM, Antunes MM, Santos MM, Lopes MAF, et al. 2016.. Combination of mass cytometry and imaging analysis reveals origin, location, and functional repopulation of liver myeloid cells in mice. . Gastroenterology 151:(6):117691
    [Crossref] [Google Scholar]
  23. 23.
    Gola A, Dorrington MG, Speranza E, Sala C, Shih RM, et al. 2021.. Commensal-driven immune zonation of the liver promotes host defence. . Nature 589:(7840):13136
    [Crossref] [Google Scholar]
  24. 24.
    English K, Tan SY, Kwan R, Holz LE, Sierro F, et al. 2022.. The liver contains distinct interconnected networks of CX3CR1+ macrophages, XCR1+ type 1 and CD301a+ type 2 conventional dendritic cells embedded within portal tracts. . Immunol. Cell Biol. 100:(6):394408
    [Crossref] [Google Scholar]
  25. 25.
    Prickett TCR, Mckenzie JL, Hart DNJ. 1988.. Characterization of interstitial dendritic cells in human liver. . Transplantation 46:(5):75461
    [Crossref] [Google Scholar]
  26. 26.
    Creus AD, Abe M, Lau AH, Hackstein H, Raimondi G, Thomson AW. 2005.. Low TLR4 expression by liver dendritic cells correlates with reduced capacity to activate allogeneic T cells in response to endotoxin. . J. Immunol. 174:(4):203745
    [Crossref] [Google Scholar]
  27. 27.
    Goddard S, Youster J, Morgan E, Adams DH. 2004.. Interleukin-10 secretion differentiates dendritic cells from human liver and skin. . Am. J. Pathol. 164:(2):51119
    [Crossref] [Google Scholar]
  28. 28.
    Pillarisetty VG, Shah AB, Miller G, Bleier JI, DeMatteo RP. 2004.. Liver dendritic cells are less immunogenic than spleen dendritic cells because of differences in subtype composition. . J. Immunol. 172:(2):100917
    [Crossref] [Google Scholar]
  29. 29.
    Bénéchet AP, Simone GD, Lucia PD, Cilenti F, Barbiera G, et al. 2019.. Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming. . Nature 574:(7777):2005
    [Crossref] [Google Scholar]
  30. 30.
    Isogawa M, Chung J, Murata Y, Kakimi K, Chisari FV. 2013.. CD40 activation rescues antiviral CD8+ T cells from PD-1-mediated exhaustion. . PLOS Pathog. 9:(7):e1003490
    [Crossref] [Google Scholar]
  31. 31.
    Murata Y, Kawashima K, Sheikh K, Tanaka Y, Isogawa M. 2018.. Intrahepatic cross-presentation and hepatocellular antigen presentation play distinct roles in the induction of hepatitis B virus–specific CD8+ T cell responses. . J. Virol. 92:(21):e00920-18
    [Crossref] [Google Scholar]
  32. 32.
    Bonnardel J, T'Jonck W, Gaublomme D, Browaeys R, Scott CL, et al. 2019.. Stellate cells, hepatocytes, and endothelial cells imprint the Kupffer cell identity on monocytes colonizing the liver macrophage niche. . Immunity 51:(4):63854.e9
    [Crossref] [Google Scholar]
  33. 33.
    Knolle PA. 2016.. Staying local—antigen presentation in the liver. . Curr. Opin. Immunol. 40::3642
    [Crossref] [Google Scholar]
  34. 34.
    Crispe IN. 2011.. Liver antigen-presenting cells. . J. Hepatol. 54:(2):35765
    [Crossref] [Google Scholar]
  35. 35.
    Heymann F, Peusquens J, Ludwig-Portugall I, Kohlhepp M, Ergen C, et al. 2015.. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. . Hepatology 62:(1):27991
    [Crossref] [Google Scholar]
  36. 36.
    Klein I, Crispe IN. 2006.. Complete differentiation of CD8+ T cells activated locally within the transplanted liver. . J. Exp. Med. 203:(2):43747
    [Crossref] [Google Scholar]
  37. 37.
    Aizarani N, Saviano A, Sagar Mailly L, Durand S, et al. 2019.. A human liver cell atlas reveals heterogeneity and epithelial progenitors. . Nature 572:(7768):199204
    [Crossref] [Google Scholar]
  38. 38.
    Liang Y, Kaneko K, Xin B, Lee J, Sun X, et al. 2022.. Temporal analyses of postnatal liver development and maturation by single-cell transcriptomics. . Dev. Cell 57:(3):398414.e5
    [Crossref] [Google Scholar]
  39. 39.
    MacParland SA, Liu JC, Ma X-Z, Innes BT, Bartczak AM, et al. 2018.. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. . Nat. Commun. 9:(1):4383
    [Crossref] [Google Scholar]
  40. 40.
    Ramachandran P, Dobie R, Wilson-Kanamori JR, Dora EF, Henderson BEP, et al. 2019.. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. . Nature 575:(7783):51218
    [Crossref] [Google Scholar]
  41. 41.
    Su Q, Kim SY, Adewale F, Zhou Y, Aldler C, et al. 2021.. Single-cell RNA transcriptome landscape of hepatocytes and non-parenchymal cells in healthy and NAFLD mouse liver. . iScience 24:(11):103233
    [Crossref] [Google Scholar]
  42. 42.
    Su X, Shi Y, Zou X, Lu Z-N, Xie G, et al. 2017.. Single-cell RNA-Seq analysis reveals dynamic trajectories during mouse liver development. . BMC Genom. 18:(1):946
    [Crossref] [Google Scholar]
  43. 43.
    Wu X, Hollingshead N, Roberto J, Knupp A, Kenerson H, et al. 2020.. Human liver macrophage subsets defined by CD32. . Front. Immunol. 11::2108
    [Crossref] [Google Scholar]
  44. 44.
    Blériot C, Barreby E, Dunsmore G, Ballaire R, Chakarov S, et al. 2021.. A subset of Kupffer cells regulates metabolism through the expression of CD36. . Immunity 54:(9):210116.e6
    [Crossref] [Google Scholar]
  45. 45.
    Simone GD, Andreata F, Bleriot C, Fumagalli V, Laura C, et al. 2021.. Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming. . Immunity 54:(9):2089100.e8
    [Crossref] [Google Scholar]
  46. 46.
    Sørensen KK, Simon-Santamaria J, McCuskey RS, Smedsrød B. 2015.. Liver sinusoidal endothelial cells. . Compr. Physiol. 5:(4):175174
    [Crossref] [Google Scholar]
  47. 47.
    Limmer A, Ohl J, Kurts C, Ljunggren H-G, Reiss Y, et al. 2000.. Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. . Nat. Med. 6:(12):134854
    [Crossref] [Google Scholar]
  48. 48.
    Knolle PA, Schmitt E, Jin S, Germann T, Duchmann R, et al. 1999.. 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. . Gastroenterology 116:(6):142840
    [Crossref] [Google Scholar]
  49. 49.
    Kruse N, Neumann K, Schrage A, Derkow K, Schott E, et al. 2009.. Priming of CD4+ T cells by liver sinusoidal endothelial cells induces CD25low forkhead box protein 3 regulatory T cells suppressing autoimmune hepatitis. . Hepatology 50:(6):190413
    [Crossref] [Google Scholar]
  50. 50.
    Winau F, Hegasy G, Weiskirchen R, Weber S, Cassan C, et al. 2007.. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. . Immunity 26:(1):11729
    [Crossref] [Google Scholar]
  51. 51.
    von Andrian UH, Mempel TR. 2003.. Homing and cellular traffic in lymph nodes. . Nat. Rev. Immunol. 3:(11):86778
    [Crossref] [Google Scholar]
  52. 52.
    Guidotti LG, Inverso D, Sironi L, Di Lucia P, Fioravanti J, et al. 2015.. Immunosurveillance of the liver by intravascular effector CD8+ T cells. . Cell 161:(3):486500
    [Crossref] [Google Scholar]
  53. 53.
    Ando K, Guidotti LG, Cerny A, Ishikawa T, Chisari FV. 1994.. CTL access to tissue antigen is restricted in vivo. . J. Immunol. 153:(2):48288
    [Crossref] [Google Scholar]
  54. 54.
    Bertolino P, Heath WR, Hardy CL, Morahan G, Miller JFAP. 1995.. Peripheral deletion of autoreactive CD8+ T cells in transgenic mice expressing H-2Kb in the liver. . Eur. J. Immunol. 25:(7):193242
    [Crossref] [Google Scholar]
  55. 55.
    Bertolino P, Bowen DG, McCaughan GW, Fazekas de St. Groth B. 2001.. Antigen-specific primary activation of CD8+ T cells within the liver. . J. Immunol. 166:(9):543038
    [Crossref] [Google Scholar]
  56. 56.
    Bowen DG, Zen M, Holz L, Davis T, McCaughan GW, Bertolino P. 2004.. The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. . J. Clin. Investig. 114:(5):70112
    [Crossref] [Google Scholar]
  57. 57.
    Holz LE, Benseler V, Bowen DG, Bouillet P, Strasser A, et al. 2008.. Intrahepatic murine CD8 T-cell activation associates with a distinct phenotype leading to Bim-dependent death. . Gastroenterology 135:(3):98997
    [Crossref] [Google Scholar]
  58. 58.
    Lopes AR, Kellam P, Das A, Dunn C, Kwan A, et al. 2008.. Bim-mediated deletion of antigen-specific CD8+ T cells in patients unable to control HBV infection. . J. Clin. Investig. 118:(5):183545
    [Crossref] [Google Scholar]
  59. 59.
    Benseler V, Warren A, Vo M, Holz LE, Tay SS, et al. 2011.. Hepatocyte entry leads to degradation of autoreactive CD8 T cells. . PNAS 108:(40):1673540
    [Crossref] [Google Scholar]
  60. 60.
    Ishak K, Baptista A, Bianchi L, Callea F, Groote JD, et al. 1995.. Histological grading and staging of chronic hepatitis. . J. Hepatol. 22:(6):69699
    [Crossref] [Google Scholar]
  61. 61.
    Kawashima K, Isogawa M, Onishi M, Baudi I, Saito S, et al. 2021.. Restoration of type I interferon signaling in intrahepatically primed CD8+ T cells promotes functional differentiation. . JCI Insight 6:(3):e145761
    [Crossref] [Google Scholar]
  62. 62.
    Wolski D, Foote PK, Chen DY, Lewis-Ximenez LL, Fauvelle C, et al. 2017.. Early transcriptional divergence marks virus-specific primary human CD8+ T cells in chronic versus acute infection. . Immunity 47:(4):64863.e8
    [Crossref] [Google Scholar]
  63. 63.
    Fisicaro P, Barili V, Montanini B, Acerbi G, Ferracin M, et al. 2017.. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. . Nat. Med. 23:(3):32736
    [Crossref] [Google Scholar]
  64. 64.
    Cheng Y, Zhu YO, Becht E, Aw P, Chen J, et al. 2019.. Multifactorial heterogeneity of virus-specific T cells and association with the progression of human chronic hepatitis B infection. . Sci. Immunol. 4:(32):eaau6905
    [Crossref] [Google Scholar]
  65. 65.
    Li H, van der Leun AM, Yofe I, Lubling Y, Gelbard-Solodkin D, et al. 2018.. Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma. . Cell 176:(4):77589.e18
    [Crossref] [Google Scholar]
  66. 66.
    Brummelman J, Mazza EMC, Alvisi G, Colombo FS, Grilli A, et al. 2018.. High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors. . J. Exp. Med. 215:(10):252035
    [Crossref] [Google Scholar]
  67. 67.
    Zheng C, Zheng L, Yoo J-K, Guo H, Zhang Y, et al. 2017.. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. . Cell 169:(7):134256.e16
    [Crossref] [Google Scholar]
  68. 68.
    Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, et al. 2019.. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. . Nature 571:(7764):26569
    [Crossref] [Google Scholar]
  69. 69.
    Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, et al. 2019.. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. . Nature 571:(7764):21118
    [Crossref] [Google Scholar]
  70. 70.
    Zander R, Schauder D, Xin G, Nguyen C, Wu X, et al. 2019.. CD4+ T cell help is required for the formation of a cytolytic CD8+ T cell subset that protects against chronic infection and cancer. . Immunity 51:(6):102842.e4
    [Crossref] [Google Scholar]
  71. 71.
    Hudson WH, Gensheimer J, Hashimoto M, Wieland A, Valanparambil RM, et al. 2019.. Proliferating transitory T cells with an effector-like transcriptional signature emerge from PD-1+ stem-like CD8+ T cells during chronic infection. . Immunity 51:(6):104358.e4
    [Crossref] [Google Scholar]
  72. 72.
    Chen Z, Ji Z, Ngiow SF, Manne S, Cai Z, et al. 2019.. TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision. . Immunity 51:(5):84055.e5
    [Crossref] [Google Scholar]
  73. 73.
    Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE, et al. 2016.. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. . Immunity 45:(2):35873
    [Crossref] [Google Scholar]
  74. 74.
    Barili V, Fisicaro P, Montanini B, Acerbi G, Filippi A, et al. 2020.. Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection. . Nat. Commun. 11:(1):604
    [Crossref] [Google Scholar]
  75. 75.
    Schurich A, Pallett LJ, Jajbhay D, Wijngaarden J, Otano I, et al. 2016.. Distinct metabolic requirements of exhausted and functional virus-specific CD8 T cells in the same host. . Cell Rep. 16:(5):124352
    [Crossref] [Google Scholar]
  76. 76.
    Swadling L, Pallett LJ, Diniz MO, Baker JM, Amin OE, et al. 2020.. Human liver memory CD8+ T cells use autophagy for tissue residence. . Cell Rep. 30:(3):68798.e6
    [Crossref] [Google Scholar]
  77. 77.
    Acerbi G, Montali I, Ferrigno GD, Barili V, Schivazappa S, et al. 2021.. Functional reconstitution of HBV-specific CD8 T cells by in vitro polyphenol treatment in chronic hepatitis B. . J. Hepatol. 74:(4):78393
    [Crossref] [Google Scholar]
  78. 78.
    Montali I, Berti CC, Morselli M, Acerbi G, Barili V, et al. 2023.. Deregulated intracellular pathways define novel molecular targets for HBV-specific CD8 T cell reconstitution in chronic hepatitis B. . J. Hepatol. 79:(1):5060
    [Crossref] [Google Scholar]
  79. 79.
    Das A, Hoare M, Davies N, Lopes AR, Dunn C, et al. 2008.. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. . J. Exp. Med. 205:(9):211124
    [Crossref] [Google Scholar]
  80. 80.
    Sandalova E, Laccabue D, Boni C, Watanabe T, Tan A, et al. 2012.. Increased levels of arginase in patients with acute hepatitis B suppress antiviral T cells. . Gastroenterology 143:(1):7887.e3
    [Crossref] [Google Scholar]
  81. 81.
    Pallett LJ, Gill US, Quaglia A, Sinclair LV, Jover-Cobos M, et al. 2015.. Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. . Nat. Med. 21:(6):591600
    [Crossref] [Google Scholar]
  82. 82.
    Schmidt NM, Wing PAC, Diniz MO, Pallett LJ, Swadling L, et al. 2021.. Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint. . Nat. Commun. 12:(1):2814
    [Crossref] [Google Scholar]
  83. 83.
    Andreata F, Moynihan KD, Fumagalli V, Di Lucia P, Pappas DC, et al. 2024.. CD8 cis-targeted IL-2 drives potent antiviral activity against hepatitis B virus. . Sci. Transl. Med. 16:(729):eadi1572
    [Crossref] [Google Scholar]
  84. 84.
    Bertolino P, Trescol-Biémont MC, Thomas J, Fazekas de St. Groth B, Pihlgren M, et al. 1999.. Death by neglect as a deletional mechanism of peripheral tolerance. . Int. Immunol. 11:(8):122538
    [Crossref] [Google Scholar]
  85. 85.
    Pol JG, Caudana P, Paillet J, Piaggio E, Kroemer G. 2020.. Effects of interleukin-2 in immunostimulation and immunosuppression. . J. Exp. Med. 217:(1):e20191247
    [Crossref] [Google Scholar]
  86. 86.
    Blattman JN, Grayson JM, Wherry EJ, Kaech SM, Smith KA, Ahmed R. 2003.. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. . Nat. Med. 9:(5):54047
    [Crossref] [Google Scholar]
  87. 87.
    West EE, Jin H-T, Rasheed A-U, Penaloza-MacMaster P, Ha S-J, et al. 2013.. PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. . J. Clin. Investig. 123:(6):260415
    [Crossref] [Google Scholar]
  88. 88.
    Fumagalli V, Lucia PD, Venzin V, Bono EB, Jordan R, et al. 2020.. Serum HBsAg clearance has minimal impact on CD8+ T cell responses in mouse models of HBV infection. . J. Exp. Med. 217:(11):e20200298
    [Crossref] [Google Scholar]
  89. 89.
    Ganem D, Prince AM. 2004.. Hepatitis B virus infection—natural history and clinical consequences. . N. Engl. J. Med. 350:(11):111829
    [Crossref] [Google Scholar]
  90. 90.
    Kuipery A, Gehring AJ, Isogawa M. 2020.. Mechanisms of HBV immune evasion. . Antivir. Res. 179::104816
    [Crossref] [Google Scholar]
  91. 91.
    Kennedy PTF, Sandalova E, Jo J, Gill U, Ushiro-Lumb I, et al. 2012.. Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B. . Gastroenterology 143:(3):63745
    [Crossref] [Google Scholar]
  92. 92.
    Shimizu Y, Guidotti LG, Fowler P, Chisari FV. 1998.. Dendritic cell immunization breaks cytotoxic T lymphocyte tolerance in hepatitis B virus transgenic mice. . J. Immunol. 161:(9):452029
    [Crossref] [Google Scholar]
  93. 93.
    Kakimi K, Isogawa M, Chung J, Sette A, Chisari FV. 2002.. Immunogenicity and tolerogenicity of hepatitis B virus structural and nonstructural proteins: implications for immunotherapy of persistent viral infections. . J. Virol. 76:(17):860920
    [Crossref] [Google Scholar]
  94. 94.
    Guidotti LG, Iannacone M. 2013.. Effector CD8 T cell trafficking within the liver. . Mol. Immunol. 55:(1):9499
    [Crossref] [Google Scholar]
  95. 95.
    Iannacone M. 2015.. Hepatic effector CD8+ T-cell dynamics. . Cell. Mol. Immunol. 12:(3):26972
    [Crossref] [Google Scholar]
  96. 96.
    Inverso D, Iannacone M. 2016.. Spatiotemporal dynamics of effector CD8+ T cell responses within the liver. . J. Leukocyte Biol. 99:(1):5155
    [Crossref] [Google Scholar]
  97. 97.
    Benechet AP, Iannacone M. 2017.. Determinants of hepatic effector CD8+ T cell dynamics. . J. Hepatol. 66:(1):22833
    [Crossref] [Google Scholar]
  98. 98.
    Guidotti LG. 2002.. The role of cytotoxic T cells and cytokines in the control of hepatitis B virus infection. . Vaccine 20::A8082
    [Crossref] [Google Scholar]
  99. 99.
    Fioravanti J, Lucia PD, Magini D, Moalli F, Boni C, et al. 2017.. Effector CD8+ T cell–derived interleukin-10 enhances acute liver immunopathology. . J. Hepatol. 67:(3):54348
    [Crossref] [Google Scholar]
  100. 100.
    Iannacone M, Guidotti LG. 2015.. Mouse models of hepatitis B virus pathogenesis. Cold Spring Harb. . Perspect. Med. 5:(11):a021477
    [Google Scholar]
  101. 101.
    Ando K, Guidotti LG, Wirth S, Ishikawa T, Missale G, et al. 1994.. Class I–restricted cytotoxic T lymphocytes are directly cytopathic for their target cells in vivo. . J. Immunol. 152:(7):324553
    [Crossref] [Google Scholar]
  102. 102.
    Guidotti LG, Rochford R, Chung J, Shapiro M, Purcell R, Chisari FV. 1999.. Viral clearance without destruction of infected cells during acute HBV infection. . Science 284:(5415):82529
    [Crossref] [Google Scholar]
  103. 103.
    Wieland SF, Spangenberg HC, Thimme R, Purcell RH, Chisari FV. 2004.. Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees. . PNAS 101:(7):212934
    [Crossref] [Google Scholar]
  104. 104.
    Guidotti LG, Ishikawa T, Hobbs MV, Matzke B, Schreiber R, Chisari FV. 1996.. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. . Immunity 4:(1):2536
    [Crossref] [Google Scholar]
  105. 105.
    Xia Y, Stadler D, Lucifora J, Reisinger F, Webb D, et al. 2016.. Interferon-γ and tumor necrosis factor-α produced by T cells reduce the HBV persistence form, cccDNA, without cytolysis. . Gastroenterology 150:(1):194205
    [Crossref] [Google Scholar]
  106. 106.
    Isogawa M, Furuichi Y, Chisari FV. 2005.. Oscillating CD8+ T cell effector functions after antigen recognition in the liver. . Immunity 23:(1):5363
    [Crossref] [Google Scholar]
  107. 107.
    Gilles PN, Fey G, Chisari FV. 1992.. Tumor necrosis factor alpha negatively regulates hepatitis B virus gene expression in transgenic mice. . J. Virol. 66:(6):395560
    [Crossref] [Google Scholar]
  108. 108.
    Guidotti LG, Ando K, Hobbs MV, Ishikawa T, Runkel L, et al. 1994.. Cytotoxic T lymphocytes inhibit hepatitis B virus gene expression by a noncytolytic mechanism in transgenic mice. . PNAS 91:(9):376468
    [Crossref] [Google Scholar]
  109. 109.
    Nakamoto Y, Guidotti LG, Pasquetto V, Schreiber RD, Chisari FV. 1997.. Differential target cell sensitivity to CTL-activated death pathways in hepatitis B virus transgenic mice. . J. Immunol. 158:(12):569297
    [Crossref] [Google Scholar]
  110. 110.
    Sitia G, Iannacone M, Aiolfi R, Isogawa M, van Rooijen N, et al. 2011.. Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. . PLOS Pathog. 7:(6):e1002061
    [Crossref] [Google Scholar]
  111. 111.
    Sitia G, Iannacone M, Müller S, Bianchi ME, Guidotti LG. 2007.. Treatment with HMGB1 inhibitors diminishes CTL-induced liver disease in HBV transgenic mice. . J. Leukocyte Biol. 81:(1):1007
    [Crossref] [Google Scholar]
  112. 112.
    Sitia G, Isogawa M, Kakimi K, Wieland SF, Chisari FV, Guidotti LG. 2002.. Depletion of neutrophils blocks the recruitment of antigen-nonspecific cells into the liver without affecting the antiviral activity of hepatitis B virus–specific cytotoxic T lymphocytes. . PNAS 99:(21):1371722
    [Crossref] [Google Scholar]
  113. 113.
    Sitia G, Isogawa M, Iannacone M, Campbell IL, Chisari FV, Guidotti LG. 2004.. MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs. . J. Clin. Investig. 113:(8):115867
    [Crossref] [Google Scholar]
  114. 114.
    Kakimi K, Lane TE, Wieland S, Asensio VC, Campbell IL, et al. 2001.. Blocking chemokine responsive to γ-2/interferon (IFN)-γ inducible protein and monokine induced by IFN-γ activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus–specific cytotoxic T lymphocytes. . J. Exp. Med. 194:(12):175566
    [Crossref] [Google Scholar]
  115. 115.
    Maini MK, Boni C, Lee CK, Larrubia JR, Reignat S, et al. 2000.. The role of virus-specific CD8+ cells in liver damage and viral control during persistent hepatitis B virus infection. . J. Exp. Med. 191:(8):126980
    [Crossref] [Google Scholar]
  116. 116.
    Fisicaro P, Barili V, Rossi M, Montali I, Vecchi A, et al. 2020.. Pathogenetic mechanisms of T cell dysfunction in chronic HBV infection and related therapeutic approaches. . Front. Immunol. 11::849
    [Crossref] [Google Scholar]
  117. 117.
    Baudi I, Kawashima K, Isogawa M. 2021.. HBV-specific CD8+ T-cell tolerance in the liver. . Front. Immunol. 12::721975
    [Crossref] [Google Scholar]
  118. 118.
    Fumagalli V, Venzin V, Lucia PD, Moalli F, Ficht X, et al. 2022.. Group 1 ILCs regulate T cell–mediated liver immunopathology by controlling local IL-2 availability. . Sci. Immunol. 7:(68):eabi6112
    [Crossref] [Google Scholar]
  119. 119.
    Rabinovich BA, Li J, Shannon J, Hurren R, Chalupny J, et al. 2003.. Activated, but not resting, T cells can be recognized and killed by syngeneic NK cells. . J. Immunol. 170:(7):357276
    [Crossref] [Google Scholar]
  120. 120.
    Soderquest K, Walzer T, Zafirova B, Klavinskis LS, Polić B, et al. 2011.. CD8+ T cell priming in the absence of NK cells leads to enhanced memory responses. . J. Immunol. 186:(6):33048
    [Crossref] [Google Scholar]
  121. 121.
    Waggoner SN, Taniguchi RT, Mathew PA, Kumar V, Welsh RM. 2010.. Absence of mouse 2B4 promotes NK cell–mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis. . J. Clin. Investig. 120:(6):192538
    [Crossref] [Google Scholar]
  122. 122.
    Lang PA, Lang KS, Xu HC, Grusdat M, Parish IA, et al. 2012.. Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity. . PNAS 109:(4):121015
    [Crossref] [Google Scholar]
  123. 123.
    Peppa D, Gill US, Reynolds G, Easom NJW, Pallett LJ, et al. 2013.. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell–mediated deletion. . J. Exp. Med. 210:(1):99114
    [Crossref] [Google Scholar]
  124. 124.
    Crouse J, Bedenikovic G, Wiesel M, Ibberson M, Xenarios I, et al. 2014.. Type I interferons protect T cells against NK cell attack mediated by the activating receptor NCR1. . Immunity 40:(6):96173
    [Crossref] [Google Scholar]
  125. 125.
    Xu HC, Grusdat M, Pandyra AA, Polz R, Huang J, et al. 2014.. Type I interferon protects antiviral CD8+ T cells from NK cell cytotoxicity. . Immunity 40:(6):94960
    [Crossref] [Google Scholar]
  126. 126.
    Cook KD, Whitmire JK. 2013.. The depletion of NK cells prevents T cell exhaustion to efficiently control disseminating virus infection. . J. Immunol. 190:(2):64149
    [Crossref] [Google Scholar]
  127. 127.
    Andrews DM, Estcourt MJ, Andoniou CE, Wikstrom ME, Khong A, et al. 2010.. Innate immunity defines the capacity of antiviral T cells to limit persistent infection. . J. Exp. Med. 207:(6):133343
    [Crossref] [Google Scholar]
  128. 128.
    Hayakawa Y, Screpanti V, Yagita H, Grandien A, Ljunggren H-G, et al. 2004.. NK cell TRAIL eliminates immature dendritic cells in vivo and limits dendritic cell vaccination efficacy. . J. Immunol. 172:(1):12329
    [Crossref] [Google Scholar]
  129. 129.
    Reignat S, Webster GJM, Brown D, Ogg GS, King A, et al. 2002.. Escaping high viral load exhaustion: CD8 cells with altered tetramer binding in chronic hepatitis B virus infection. . J. Exp. Med. 195:(9):1089101
    [Crossref] [Google Scholar]
  130. 130.
    Webster GJM, Reignat S, Brown D, Ogg GS, Jones L, et al. 2004.. Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy. . J. Virol. 78:(11):570719
    [Crossref] [Google Scholar]
  131. 131.
    Boni C, Fisicaro P, Valdatta C, Amadei B, Vincenzo PD, et al. 2007.. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. . J. Virol. 81:(8):421525
    [Crossref] [Google Scholar]
  132. 132.
    Hoogeveen RC, Robidoux MP, Schwarz T, Heydmann L, Cheney JA, et al. 2018.. Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection. . Gut 68:(5):893904
    [Crossref] [Google Scholar]
  133. 133.
    Maini MK, Boni C, Ogg GS, King AS, Reignat S, et al. 1999.. Direct ex vivo analysis of hepatitis B virus–specific CD8+ T cells associated with the control of infection. . Gastroenterology 117:(6):138696
    [Crossref] [Google Scholar]
  134. 134.
    Guidotti LG, Isogawa M, Chisari FV. 2015.. Host-virus interactions in hepatitis B virus infection. . Curr. Opin. Immunol. 36::6166
    [Crossref] [Google Scholar]
  135. 135.
    Bertoletti A, Ferrari C. 2016.. Adaptive immunity in HBV infection. . J. Hepatol. 64:(1):S7183
    [Crossref] [Google Scholar]
  136. 136.
    Park J-J, Wong DK, Wahed AS, Lee WM, Feld JJ, et al. 2016.. Hepatitis B virus–specific and global T-cell dysfunction in chronic hepatitis B. . Gastroenterology 150:(3):68495.e5
    [Crossref] [Google Scholar]
  137. 137.
    Nakamoto Y, Guidotti LG, Kuhlen CV, Fowler P, Chisari FV. 1998.. Immune pathogenesis of hepatocellular carcinoma. . J. Exp. Med. 188:(2):34150
    [Crossref] [Google Scholar]
  138. 138.
    Sitia G, Aiolfi R, Lucia PD, Mainetti M, Fiocchi A, et al. 2012.. Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. . PNAS 109:(32):E216572
    [Crossref] [Google Scholar]
  139. 139.
    Nakamoto Y, Suda T, Momoi T, Kaneko S. 2004.. Different procarcinogenic potentials of lymphocyte subsets in a transgenic mouse model of chronic hepatitis B. . Cancer Res. 64:(9):332633
    [Crossref] [Google Scholar]
  140. 140.
    Tang LSY, Covert E, Wilson E, Kottilil S. 2018.. Chronic hepatitis B infection: a review. . JAMA 319:(17):180213
    [Crossref] [Google Scholar]
  141. 141.
    Tonnerre P, Wolski D, Subudhi S, Aljabban J, Hoogeveen RC, et al. 2021.. Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory. . Nat. Immunol. 22:(8):103041
    [Crossref] [Google Scholar]
  142. 142.
    Hensel N, Gu Z, Sagar Wieland D, Jechow K, et al. 2021.. Memory-like HCV-specific CD8+ T cells retain a molecular scar after cure of chronic HCV infection. . Nat. Immunol. 22:(2):22939
    [Crossref] [Google Scholar]
  143. 143.
    Abdel-Hakeem MS, Manne S, Beltra J-C, Stelekati E, Chen Z, et al. 2021.. Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation. . Nat. Immunol. 22:(8):100819
    [Crossref] [Google Scholar]
  144. 144.
    Rosato PC, Wijeyesinghe S, Stolley JM, Masopust D. 2020.. Integrating resident memory into T cell differentiation models. . Curr. Opin. Immunol. 63::3542
    [Crossref] [Google Scholar]
  145. 145.
    Konjar Š, Ficht X, Iannacone M, Veldhoen M. 2022.. Heterogeneity of tissue resident memory T cells. . Immunol. Lett. 245::17
    [Crossref] [Google Scholar]
  146. 146.
    Steinert EM, Schenkel JM, Fraser KA, Beura LK, Manlove LS, et al. 2015.. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. . Cell 161:(4):73749
    [Crossref] [Google Scholar]
  147. 147.
    Pallett LJ, Davies J, Colbeck EJ, Robertson F, Hansi N, et al. 2017.. IL-2high tissue-resident T cells in the human liver: sentinels for hepatotropic infection. . J. Exp. Med. 214:(6):156780
    [Crossref] [Google Scholar]
  148. 148.
    Holz LE, Prier JE, Freestone D, Steiner TM, English K, et al. 2018.. 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. . Cell Rep. 25:(1):6879.e4
    [Crossref] [Google Scholar]
  149. 149.
    Mackay LK, Rahimpour A, Ma JZ, Collins N, Stock AT, et al. 2013.. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. . Nat. Immunol. 14:(12):1294301
    [Crossref] [Google Scholar]
  150. 150.
    Tse S-W, Radtke AJ, Espinosa DA, Cockburn IA, Zavala F. 2014.. The chemokine receptor CXCR6 is required for the maintenance of liver memory CD8+ T cells specific for infectious pathogens. . J. Infect. Dis. 210:(9):150816
    [Crossref] [Google Scholar]
  151. 151.
    Oo YH, Adams DH. 2009.. The role of chemokines in the recruitment of lymphocytes to the liver. . J. Autoimmun. 34:(1):4554
    [Crossref] [Google Scholar]
  152. 152.
    Fernandez-Ruiz D, Ng WY, Holz LE, Ma JZ, Zaid A, et al. 2016.. Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection. . Immunity 45:(4):889902
    [Crossref] [Google Scholar]
  153. 153.
    McNamara HA, Cai Y, Wagle MV, Sontani Y, Roots CM, et al. 2017.. Up-regulation of LFA-1 allows liver-resident memory T cells to patrol and remain in the hepatic sinusoids. . Sci. Immunol. 2:(9):eaaj1996
    [Crossref] [Google Scholar]
  154. 154.
    Schenkel JM, Fraser KA, Beura LK, Pauken KE, Vezys V, Masopust D. 2014.. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. . Science 346:(6205):98101
    [Crossref] [Google Scholar]
  155. 155.
    Shoukry NH, Grakoui A, Houghton M, Chien DY, Ghrayeb J, et al. 2003.. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. . J. Exp. Med. 197:(12):164555
    [Crossref] [Google Scholar]
  156. 156.
    Ishizuka AS, Lyke KE, DeZure A, Berry AA, Richie TL, et al. 2016.. Protection against malaria at 1 year and immune correlates following PfSPZ vaccination. . Nat. Med. 22:(6):61423
    [Crossref] [Google Scholar]
  157. 157.
    Cheng Y, Gunasegaran B, Singh HD, Dutertre C-A, Loh CY, et al. 2021.. Non-terminally exhausted tumor-resident memory HBV-specific T cell responses correlate with relapse-free survival in hepatocellular carcinoma. . Immunity 54:(8):182540.e7
    [Crossref] [Google Scholar]
  158. 158.
    Dudek M, Pfister D, Donakonda S, Filpe P, Schneider A, et al. 2021.. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. . Nature 592:(7854):44449
    [Crossref] [Google Scholar]
  159. 159.
    Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, et al. 2021.. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. . Nature 592:(7854):45056
    [Crossref] [Google Scholar]
  160. 160.
    Luxenburger H, Neumann-Haefelin C. 2023.. Liver-resident CD8+ T cells in viral hepatitis: not always good guys. . J. Clin. Investig. 133:(1):e165033
    [Crossref] [Google Scholar]
  161. 161.
    Nkongolo S, Mahamed D, Kuipery A, Vasquez JDS, Kim SC, et al. 2023.. Longitudinal liver sampling in patients with chronic hepatitis B starting antiviral therapy reveals hepatotoxic CD8+ T cells. . J. Clin. Investig. 133:(1):e158903
    [Crossref] [Google Scholar]
  162. 162.
    Pallett LJ, Burton AR, Amin OE, Rodriguez-Tajes S, Patel AA, et al. 2020.. Longevity and replenishment of human liver-resident memory T cells and mononuclear phagocytes. . J. Exp. Med. 217:(9):e20200050
    [Crossref] [Google Scholar]
  163. 163.
    Pallett LJ, Swadling L, Diniz M, Maini AA, Schwabenland M, et al. 2023.. Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS. . Nature 614:(7947):33442
    [Crossref] [Google Scholar]
  164. 164.
    Ganley M, Holz LE, Minnell JJ, de Menezes MN, Burn OK, et al. 2023. mRNA vaccine against malaria tailored for liver-resident memory T cells. . Nat. Immunol. 24::148798
    [Crossref] [Google Scholar]
  165. 165.
    Wieland S, Thimme R, Purcell RH, Chisari FV. 2004.. Genomic analysis of the host response to hepatitis B virus infection. . PNAS 101:(17):666974
    [Crossref] [Google Scholar]
  166. 166.
    Laidlaw BJ, Craft JE, Kaech SM. 2016.. The multifaceted role of CD4+ T cells in CD8+ T cell memory. . Nat. Rev. Immunol. 16:(2):10211
    [Crossref] [Google Scholar]
  167. 167.
    Asabe S, Wieland SF, Chattopadhyay PK, Roederer M, Engle RE, et al. 2009.. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. . J. Virol. 83:(19):965262
    [Crossref] [Google Scholar]
  168. 168.
    Thimme R, Oldach D, Chang K, Steiger C, Ray S, Chisari F. 2001.. Determinants of viral clearance and persistence during acute hepatitis C virus infection. . J. Exp. Med. 194:(10):1395406
    [Crossref] [Google Scholar]
  169. 169.
    Ulsenheimer A, Gerlach JT, Gruener NH, Jung M, Schirren C, et al. 2003.. Detection of functionally altered hepatitis C virus–specific CD4+ T cells in acute and chronic hepatitis C. . Hepatology 37:(5):118998
    [Crossref] [Google Scholar]
  170. 170.
    Grakoui A, Shoukry NH, Woollard DJ, Han J-H, Hanson HL, et al. 2003.. HCV persistence and immune evasion in the absence of memory T cell help. . Science 302:(5645):65962
    [Crossref] [Google Scholar]
  171. 171.
    Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, et al. 2003.. CD8+ T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. . J. Virol. 77:(1):6876
    [Crossref] [Google Scholar]
  172. 172.
    Tay SS, Wong YC, Roediger B, Sierro F, Lu B, et al. 2014.. Intrahepatic activation of naive CD4+ T cells by liver-resident phagocytic cells. . J. Immunol. 193:(5):208795
    [Crossref] [Google Scholar]
  173. 173.
    Buxbaum J, Qian P, Allen PM, Peters MG. 2008.. Hepatitis resulting from liver-specific expression and recognition of self-antigen. . J. Autoimmun. 31:(3):20815
    [Crossref] [Google Scholar]
  174. 174.
    Derkow K, Loddenkemper C, Mintern J, Kruse N, Klugewitz K, et al. 2007.. Differential priming of CD8 and CD4 T-cells in animal models of autoimmune hepatitis and cholangitis. . Hepatology 46:(4):115565
    [Crossref] [Google Scholar]
  175. 175.
    Wuensch SA, Spahn J, Crispe IN. 2010.. Direct, help-independent priming of CD8+ T cells by adeno-associated virus-transduced hepatocytes. . Hepatology 52:(3):106877
    [Crossref] [Google Scholar]
  176. 176.
    Mizukoshi E, Sidney J, Livingston B, Ghany M, Hoofnagle JH, et al. 2004.. Cellular immune responses to the hepatitis B virus polymerase. . J. Immunol. 173:(9):586371
    [Crossref] [Google Scholar]
  177. 177.
    Dong Y, Li X, Zhang L, Zhu Q, Chen C, et al. 2019.. CD4+ T cell exhaustion revealed by high PD-1 and LAG-3 expression and the loss of helper T cell function in chronic hepatitis B. . BMC Immunol. 20:(1):27
    [Crossref] [Google Scholar]
  178. 178.
    Kim JH, Ghosh A, Ayithan N, Romani S, Khanam A, et al. 2020.. Circulating serum HBsAg level is a biomarker for HBV-specific T and B cell responses in chronic hepatitis B patients. . Sci. Rep. 10:(1):1835
    [Crossref] [Google Scholar]
  179. 179.
    Ackermann C, Smits M, Woost R, Eberhard JM, Peine S, et al. 2019.. HCV-specific CD4+ T cells of patients with acute and chronic HCV infection display high expression of TIGIT and other co-inhibitory molecules. . Sci. Rep. 9:(1):10624
    [Crossref] [Google Scholar]
  180. 180.
    Fisicaro P, Valdatta C, Massari M, Loggi E, Biasini E, et al. 2010.. Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. . Gastroenterology 138:(2):68293.e4
    [Crossref] [Google Scholar]
  181. 181.
    Wang X, Dong Q, Li Q, Li Y, Zhao D, et al. 2018.. Dysregulated response of follicular helper T cells to hepatitis B surface antigen promotes HBV persistence in mice and associates with outcomes of patients. . Gastroenterology 154:(8):222236
    [Crossref] [Google Scholar]
  182. 182.
    Li Y, Ma S, Tang L, Li Y, Wang W, et al. 2013.. Circulating chemokine (C-X-C motif) receptor 5+CD4+ T cells benefit hepatitis B e antigen seroconversion through IL-21 in patients with chronic hepatitis B virus infection. . Hepatology 58:(4):127786
    [Crossref] [Google Scholar]
  183. 183.
    Wang H, Luo H, Wan X, Fu X, Mao Q, et al. 2020.. TNF-α/IFN-γ profile of HBV-specific CD4 T cells is associated with liver damage and viral clearance in chronic HBV infection. . J. Hepatol. 72:(1):4556
    [Crossref] [Google Scholar]
  184. 184.
    Hoogeveen RC, Dijkstra S, Bartsch LM, Drescher HK, Aneja J, et al. 2022.. Hepatitis B virus–specific CD4 T cell responses differentiate functional cure from chronic surface antigen+ infection. . J. Hepatol. 77:(5):127686
    [Crossref] [Google Scholar]
  185. 185.
    Li Y, Wen C, Gu S, Wang W, Guo L, et al. 2023.. Differential response of HBV envelope–specific CD4+ T cells is related to HBsAg loss after stopping nucleos(t)ide analogue therapy. . Hepatology 78:(2):592606
    [Crossref] [Google Scholar]
  186. 186.
    Su J, Brunner L, Oz EA, Sacherl J, Frank G, et al. 2023.. Activation of CD4 T cells during prime immunization determines the success of a therapeutic hepatitis B vaccine in HBV-carrier mouse models. . J. Hepatol. 78:(4):71730
    [Crossref] [Google Scholar]
  187. 187.
    Wiggins BG, Pallett LJ, Li X, Davies SP, Amin OE, et al. 2022.. The human liver microenvironment shapes the homing and function of CD4+ T-cell populations. . Gut 71:(7):1399411
    [Crossref] [Google Scholar]
  188. 188.
    Pallett LJ, Maini MK. 2022.. Liver-resident memory T cells: life in lockdown. . Semin. Immunopathol. 44:(6):81325
    [Crossref] [Google Scholar]
  189. 189.
    Oo YH, Sakaguchi S. 2013.. Regulatory T-cell directed therapies in liver diseases. . J. Hepatol. 59:(5):112734
    [Crossref] [Google Scholar]
  190. 190.
    Manigold T, Racanelli V. 2007.. T-cell regulation by CD4 regulatory T cells during hepatitis B and C virus infections: facts and controversies. . Lancet Infect. Dis. 7:(12):80413
    [Crossref] [Google Scholar]
  191. 191.
    Maini MK, Burton AR. 2019.. Restoring, releasing or replacing adaptive immunity in chronic hepatitis B. . Nat. Rev. Gastroenterol. 16:(11):66275
    [Crossref] [Google Scholar]
  192. 192.
    Loomba R, Liang TJ. 2017.. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions. . Gastroenterology 152:(6):1297309
    [Crossref] [Google Scholar]
  193. 193.
    Neumann-Haefelin C, Thimme R. 2018.. Entering the spotlight: hepatitis B surface antigen-specific B cells. . J. Clin. Investig. 128:(10):425759
    [Crossref] [Google Scholar]
  194. 194.
    Maruyama T, McLachlan A, Iino S, Koike K, Kurokawa K, Milich DR. 1993.. The serology of chronic hepatitis B infection revisited. . J. Clin. Investig. 91:(6):258695
    [Crossref] [Google Scholar]
  195. 195.
    Oliviero B, Cerino A, Varchetta S, Paudice E, Pai S, et al. 2011.. Enhanced B-cell differentiation and reduced proliferative capacity in chronic hepatitis C and chronic hepatitis B virus infections. . J. Hepatol. 55:(1):5360
    [Crossref] [Google Scholar]
  196. 196.
    Xu X, Shang Q, Chen X, Nie W, Zou Z, et al. 2015.. Reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients. . Cell. Mol. Immunol. 12:(3):30916
    [Crossref] [Google Scholar]
  197. 197.
    Burton AR, Pallett LJ, McCoy LE, Suveizdyte K, Amin OE, et al. 2018.. Circulating and intrahepatic antiviral B cells are defective in hepatitis B. . J. Clin. Investig. 128:(10):4588603
    [Crossref] [Google Scholar]
  198. 198.
    Salimzadeh L, Bert NL, Dutertre C-A, Gill US, Newell EW, et al. 2018.. PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection. . J. Clin. Investig. 128:(10):457387
    [Crossref] [Google Scholar]
  199. 199.
    Burton AR, Maini MK. 2021.. Human antiviral B cell responses: emerging lessons from hepatitis B and COVID-19. . Immunol. Rev. 299:(1):10817
    [Crossref] [Google Scholar]
  200. 200.
    Trivedi N, Weisel F, Smita S, Joachim S, Kader M, et al. 2019.. Liver is a generative site for the B cell response to Ehrlichia muris. . Immunity 51:(6):1088101.e5
    [Crossref] [Google Scholar]
  201. 201.
    Charles ED, Brunetti C, Marukian S, Ritola KD, Talal AH, et al. 2011.. Clonal B cells in patients with hepatitis C virus–associated mixed cryoglobulinemia contain an expanded anergic CD21low B-cell subset. . Blood 117:(20):542537
    [Crossref] [Google Scholar]
  202. 202.
    Chang L-Y, Li Y, Kaplan DE. 2017.. Hepatitis C viraemia reversibly maintains subset of antigen-specific T-bet+ tissue-like memory B cells. . J. Viral Hepat. 24:(5):38996
    [Crossref] [Google Scholar]
  203. 203.
    Tucci FA, Broering R, Lutterbeck M, Schlaak JF, Küppers R. 2014.. Intrahepatic B-cell follicles of chronically hepatitis C virus–infected individuals lack signs of an ectopic germinal center reaction. . Eur. J. Immunol. 44:(6):184250
    [Crossref] [Google Scholar]
  204. 204.
    de Ruiter PE, van der Laan LJW. 2015.. Evidence of B-cell follicles with germinal centers in chronic hepatitis C patients. . Eur. J. Immunol. 45:(5):157071
    [Crossref] [Google Scholar]
  205. 205.
    Llovet JM, Castet F, Heikenwalder M, Maini MK, Mazzaferro V, et al. 2022.. Immunotherapies for hepatocellular carcinoma. . Nat. Rev. Clin. Oncol. 19:(3):15172
    [Crossref] [Google Scholar]
  206. 206.
    Finkin S, Yuan D, Stein I, Taniguchi K, Weber A, et al. 2015.. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. . Nat. Immunol. 16:(12):123544
    [Crossref] [Google Scholar]
  207. 207.
    Das A, Ellis G, Pallant C, Lopes AR, Khanna P, et al. 2012.. IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. . J. Immunol. 189:(8):392535
    [Crossref] [Google Scholar]
  208. 208.
    Xue H, Lin F, Tan H, Zhu Z-Q, Zhang Z-Y, Zhao L. 2016.. Overrepresentation of IL-10-expressing B cells suppresses cytotoxic CD4+ T cell activity in HBV-induced hepatocellular carcinoma. . PLOS ONE 11:(5):e0154815
    [Crossref] [Google Scholar]
  209. 209.
    Calderaro J, Petitprez F, Becht E, Laurent A, Hirsch TZ, et al. 2019.. Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma. . J. Hepatol. 70:(1):5865
    [Crossref] [Google Scholar]
  210. 210.
    Bruno TC. 2020.. New predictors for immunotherapy responses sharpen our view of the tumour microenvironment. . Nature 577:(7791):47476
    [Crossref] [Google Scholar]
  211. 211.
    Taylor S, Assis D, Mack C. 2019.. The contribution of B cells in autoimmune liver diseases. . Semin. Liver Dis. 39:(04):42231
    [Crossref] [Google Scholar]
  212. 212.
    Iannacone M, Andreata F, Guidotti LG. 2022.. Immunological insights in the treatment of chronic hepatitis B. . Curr. Opin. Immunol. 77::102207
    [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-immunol-090122-041354
Loading
/content/journals/10.1146/annurev-immunol-090122-041354
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error