Immune Netw.  2016 Dec;16(6):330-336. 10.4110/in.2016.16.6.330.

Regulatory T Cells in Hepatitis B and C Virus Infections

• Jung MK
• Shin EC

• KMID: 2362797
• DOI: http://doi.org/10.4110/in.2016.16.6.330

Abstract

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are hepatotropic viruses that establish chronic persistent infection by effectively escaping the host immune response and can cause immune-mediated liver injury. It has recently become apparent that regulatory T (Treg) cells, specifically CD4⁺CD25⁺Foxp3⁺ Treg cells, modulate viral diseases by suppressing antiviral immune responses and regulating inflammatory host injury. The roles of Treg cells in HBV and HCV infections range from suppressing antiviral T cell responses to protecting the liver from immune-mediated damage. This review describes Treg cells and subpopulations and focuses on the roles of these cells in HBV and HCV infections.

Keyword

Regulatory T cell; Hepatitis B virus; Hepatitis C virus

MeSH Terms

Hepacivirus
Hepatitis B virus
Hepatitis B*
Hepatitis*
Liver
T-Lymphocytes, Regulatory*
United Nations
Virus Diseases

Figure

• 

  Figure 1 The subpopulation of human Treg cells. Three distinct subpopulations of human Treg cells are defined based on the expression level of CD45RA and Foxp3 as follows: CD45RA+Foxp3low resting Treg cells (subpopulation I), CD45RA−Foxp3high activated Treg cells (subpopulation II), and CD45RA−Foxp3low cytokine-secreting non-suppressive cells (subpopulation III) (32).

Reference

1. Bowen DG, Walker CM. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature. 2005; 436:946–952.

2. Dustin LB, Rice CM. Flying under the radar: the immunobiology of hepatitis C. Annu Rev Immunol. 2007; 25:71–99.

3. Wieland SF, Chisari FV. Stealth and cunning: hepatitis B and hepatitis C viruses. J Virol. 2005; 79:9369–9380.

4. Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol. 2006; 1:23–61.

5. Rehermann B, Bertoletti A. Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections. Hepatology. 2015; 61:712–721.

6. Shin EC, Sung PS, Park SH. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol. 2016; 16:509–523.

7. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 2005; 5:215–229.

8. Grakoui A, Shoukry NH, Woollard DJ, Han JH, Hanson HL, Ghrayeb J, Murthy KK, Rice CM, Walker CM. HCV persistence and immune evasion in the absence of memory T cell help. Science. 2003; 302:659–662.

9. Shoukry NH, Grakoui A, Houghton M, Chien DY, Ghrayeb J, Reimann KA, Walker CM. Memory CD8⁺ T cells are required for protection from persistent hepatitis C virus infection. J Exp Med. 2003; 197:1645–1655.

10. Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH, Chisari FV. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol. 2003; 77:68–76.

11. Park SH, Rehermann B. Immune responses to HCV and other hepatitis viruses. Immunity. 2014; 40:13–24.

12. Shevach EM, DiPaolo RA, Andersson J, Zhao DM, Stephens GL, Thornton AM. The lifestyle of naturally occurring CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells. Immunol Rev. 2006; 212:60–73.

13. Zhao DM, Thornton AM, DiPaolo RJ, Shevach EM. Activated CD4⁺CD25⁺ T cells selectively kill B lymphocytes. Blood. 2006; 107:3925–3932.

14. Ghiringhelli F, Menard C, Martin F, Zitvogel L. The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression. Immunol Rev. 2006; 214:229–238.

15. Mahnke K, Enk AH. Dendritic cells: key cells for the induction of regulatory T cells? Curr Top Microbiol Immunol. 2005; 293:133–150.

16. Suvas S, Azkur AK, Kim BS, Kumaraguru U, Rouse BT. CD4⁺CD25⁺ regulatory T cells control the severity of viral immunoinflammatory lesions. J Immunol. 2004; 172:4123–4132.

17. Suvas S, Kumaraguru U, Pack CD, Lee S, Rouse BT. CD4⁺CD25⁺ T cells regulate virus-specific primary and memory CD8⁺ T cell responses. J Exp Med. 2003; 198:889–901.

18. Choi YS, Lee J, Lee HW, Chang DY, Sung PS, Jung MK, Park JY, Kim JK, Lee JI, Park H, Cheong JY, Suh KS, Kim HJ, Lee JS, Kim KA, Shin EC. Liver injury in acute hepatitis A is associated with decreased frequency of regulatory T cells caused by Fas-mediated apoptosis. Gut. 2015; 64:1303–1313.

19. Sakaguchi S, Fukuma K, Kuribayashi K, Masuda T. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J Exp Med. 1985; 161:72–87.

20. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995; 155:1151–1164.

21. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003; 299:1057–1061.

22. Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol. 2003; 3:253–257.

23. Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, Jiang S, Kuchroo VK, Mathis D, Roncarolo MG, Rudensky A, Sakaguchi S, Shevach EM, Vignali DA, Ziegler SF. Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol. 2013; 14:307–308.

24. Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3⁺ regulatory T cells: more of the same or a division of labor? Immunity. 2009; 30:626–635.

25. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM. Conversion of peripheral CD4⁺CD25⁻ naive T cells to CD4⁺CD25⁺ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003; 198:1875–1886.

26. Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA. A role for TGF-beta in the generation and expansion of CD4⁺CD25⁺ regulatory T cells from human peripheral blood. J Immunol. 2001; 166:7282–7289.

27. Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von BH. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol. 2005; 6:1219–1227.

28. Shevach EM. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity. 2006; 25:195–201.

29. Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev. 2001; 182:207–214.

30. Billerbeck E, Blum HE, Thimme R. Parallel expansion of human virus-specific FoxP3- effector memory and de novo-generated FoxP3⁺ regulatory CD8⁺ T cells upon antigen recognition in vitro. J Immunol. 2007; 179:1039–1048.

31. Endharti AT, Rifa'I M, Shi Z, Fukuoka Y, Nakahara Y, Kawamoto Y, Takeda K, Isobe K, Suzuki H. Cutting edge: CD8⁺CD122⁺ regulatory T cells produce IL-10 to suppress IFN-gamma production and proliferation of CD8⁺ T cells. J Immunol. 2005; 175:7093–7097.

32. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, Mathian A, Nakahata T, Yamaguchi T, Nomura T, Ono M, Amoura Z, Gorochov G, Sakaguchi S. Functional delineation and differentiation dynamics of human CD4⁺ T cells expressing the FoxP3 transcription factor. Immunity. 2009; 30:899–911.

33. Miyara M, Chader D, Sage E, Sugiyama D, Nishikawa H, Bouvry D, Claer L, Hingorani R, Balderas R, Rohrer J, Warner N, Chapelier A, Valeyre D, Kannagi R, Sakaguchi S, Amoura Z, Gorochov G. Sialyl Lewis x (CD15s) identifies highly differentiated and most suppressive FOXP3high regulatory T cells in humans. Proc Natl Acad Sci U S A. 2015; 112:7225–7230.

34. Zhang M, Zhou J, Zhao T, Huang G, Tan Y, Tan S, Fu X, Niu W, Meng G, Chen X, Shang X, Liu D, Ni B, Wang L, Wu Y. Dissection of a circulating and intrahepatic CD4(+)Foxp3(+) T-cell subpopulation in chronic hepatitis B virus (HBV) infection: a highly informative strategy for distinguishing chronic HBV infection states. J Infect Dis. 2012; 205:1111–1120.

35. Yamaguchi T, Wing JB, Sakaguchi S. Two modes of immune suppression by Foxp3(+) regulatory T cells under inflammatory or non-inflammatory conditions. Semin Immunol. 2011; 23:424–430.

36. Benito JM, Lopez M, Soriano V. The role of CD8⁺ T-cell response in HIV infection. AIDS Rev. 2004; 6:79–88.

37. Goulder PJ, Watkins DI. HIV and SIV CTL escape: implications for vaccine design. Nat Rev Immunol. 2004; 4:630–640.

38. Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol. 2005; 6:353–360.

39. Mills KH. Regulatory T cells: friend or foe in immunity to infection? Nat Rev Immunol. 2004; 4:841–855.

40. Manigold T, Racanelli V. T-cell regulation by CD4 regulatory T cells during hepatitis B and C virus infections: facts and controversies. Lancet Infect Dis. 2007; 7:804–813.

41. TrehanPati N, Kotillil S, Hissar SS, Shrivastava S, Khanam A, Sukriti S, Mishra SK, Sarin SK. Circulating Tregs correlate with viral load reduction in chronic HBV-treated patients with tenofovir disoproxil fumarate. J Clin Immunol. 2011; 31:509–520.

42. Stoop JN, van der Molen RG, Baan CC, van der Laan LJ, Kuipers EJ, Kusters JG, Janssen HL. Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology. 2005; 41:771–778.

43. Franzese O, Kennedy PT, Gehring AJ, Gotto J, Williams R, Maini MK, Bertoletti A. Modulation of the CD8⁺-T-cell response by CD4⁺ CD25⁺ regulatory T cells in patients with hepatitis B virus infection. J Virol. 2005; 79:3322–3328.

44. Xu D, Fu J, Jin L, Zhang H, Zhou C, Zou Z, Zhao JM, Zhang B, Shi M, Ding X, Tang Z, Fu YX, Wang FS. Circulating and liver resident CD4⁺CD25⁺ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B. J Immunol. 2006; 177:739–747.

45. Stoop JN, van der Molen RG, Kuipers EJ, Kusters JG, Janssen HL. Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B. Virology. 2007; 361:141–148.

46. Yang G, Liu A, Xie Q, Guo TB, Wan B, Zhou B, Zhang JZ. Association of CD4⁺CD25⁺Foxp3⁺ regulatory T cells with chronic activity and viral clearance in patients with hepatitis B. Int Immunol. 2007; 19:133–140.

47. Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF. Cutting edge: TGF-beta induces a regulatory phenotype in CD4⁺CD25⁻ T cells through Foxp3 induction and down-regulation of Smad7. J Immunol. 2004; 172:5149–5153.

48. Ichikawa S, Mucida D, Tyznik AJ, Kronenberg M, Cheroutre H. Hepatic stellate cells function as regulatory bystanders. J Immunol. 2011; 186:5549–5555.

49. Smyk-Pearson S, Golden-Mason L, Klarquist J, Burton JR Jr, Tester IA, Wang CC, Culbertson N, Vandenbark AA, Rosen HR. Functional suppression by FoxP3⁺CD4⁺CD25(high) regulatory T cells during acute hepatitis C virus infection. J Infect Dis. 2008; 197:46–57.

50. Ebinuma H, Nakamoto N, Li Y, Price DA, Gostick E, Levine BL, Tobias J, Kwok WW, Chang KM. Identification and in vitro expansion of functional antigen-specific CD25⁺ FoxP3⁺ regulatory T cells in hepatitis C virus infection. J Virol. 2008; 82:5043–5053.

51. Sugimoto K, Ikeda F, Stadanlick J, Nunes FA, Alter HJ, Chang KM. Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection. Hepatology. 2003; 38:1437–1448.

52. Li S, Gowans EJ, Chougnet C, Plebanski M, Dittmer U. Natural regulatory T cells and persistent viral infection. J Virol. 2008; 82:21–30.

53. Rushbrook SM, Ward SM, Unitt E, Vowler SL, Lucas M, Klenerman P, Alexander GJ. Regulatory T cells suppress in vitro proliferation of virus-specific CD8+ T cells during persistent hepatitis C virus infection. J Virol. 2005; 79:7852–7859.

54. Ward SM, Fox BC, Brown PJ, Worthington J, Fox SB, Chapman RW, Fleming KA, Banham AH, Klenerman P. Quantification and localisation of FOXP3⁺ T lymphocytes and relation to hepatic inflammation during chronic HCV infection. J Hepatol. 2007; 47:316–324.

55. Boettler T, Spangenberg HC, Neumann-Haefelin C, Panther E, Urbani S, Ferrari C, Blum HE, von WF, Thimme R. T cells with a CD4⁺CD25⁺ regulatory phenotype suppress in vitro proliferation of virus-specific CD8⁺ T cells during chronic hepatitis C virus infection. J Virol. 2005; 79:7860–7867.

56. Claassen MA, de Knegt RJ, Tilanus HW, Janssen HL, Boonstra A. Abundant numbers of regulatory T cells localize to the liver of chronic hepatitis C infected patients and limit the extent of fibrosis. J Hepatol. 2010; 52:315–321.

57. Bolacchi F, Sinistro A, Ciaprini C, Demin F, Capozzi M, Carducci FC, Drapeau CM, Rocchi G, Bergamini A. Increased hepatitis C virus (HCV)-specific CD4⁺CD25⁺ regulatory T lymphocytes and reduced HCV-specific CD4⁺ T cell response in HCV-infected patients with normal versus abnormal alanine aminotransferase levels. Clin Exp Immunol. 2006; 144:188–196.

58. Manigold T, Shin EC, Mizukoshi E, Mihalik K, Murthy KK, Rice CM, Piccirillo CA, Rehermann B. Foxp3⁺CD4⁺CD25⁺ T cells control virus-specific memory T cells in chimpanzees that recovered from hepatitis C. Blood. 2006; 107:4424–4432.

59. Abel M, Sene D, Pol S, Bourliere M, Poynard T, Charlotte F, Cacoub P, Caillat-Zucman S. Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection. Hepatology. 2006; 44:1607–1616.

60. Accapezzato D, Francavilla V, Paroli M, Casciaro M, Chircu LV, Cividini A, Abrignani S, Mondelli MU, Barnaba V. Hepatic expansion of a virus-specific regulatory CD8(+) T cell population in chronic hepatitis C virus infection. J Clin Invest. 2004; 113:963–972.

61. Alatrakchi N, Graham CS, van d, Sherman VKE, Exley MA, Koziel MJ. Hepatitis C virus (HCV)-specific CD8⁺ cells produce transforming growth factor beta that can suppress HCV-specific T-cell responses. J Virol. 2007; 81:5882–5892.