Elevated Frequency and Function of Regulatory T Cells in Patients

Topics: Immune system, Hepatitis C, T cell Pages: 20 (6920 words) Published: June 23, 2013
J Gastroenterol DOI 10.1007/s00535-012-0544-9

ORIGINAL ARTICLE—LIVER, PANCREAS, AND BILIARY TRACT

Elevated frequency and function of regulatory T cells in patients with active chronic hepatitis C Kuo-Chih Tseng • Yun-Che Ho • Yu-Hsi Hsieh Ning-Sheng Lai • Zhi-Hong Wen • Chin Li • Shu-Fen Wu •

Received: 20 June 2011 / Accepted: 11 January 2012 Ó Springer 2012

Abstract Background Regulatory T cells (Tregs) play a pivotal role in the persistence of hepatitis C virus infection. The aim of this study was to evaluate the frequency and function of Tregs in patients with chronic hepatitis C (CHC). Methods We enrolled 44 CHC patients with elevated alanine aminotransferase (ALT) levels (CH group), 13 CHC patients with persistent normal ALT levels (PNALT group), and 14 age-matched healthy subjects (HS group; controls). Tregs were identified as CD4?, CD25?, and forkhead box P3 (Foxp3)? T lymphocytes, using threecolor fluorescence-activated cell sorting (FACS). The frequency of Tregs was determined by calculating the percentage of CD4?CD25high T cells among CD4 T cells. CD127 and CD45RA were also analyzed for subsets of Tregs. The levels of serum transforming growth factor (TGF)-b and interleukin (IL)-10 in immunosuppressive assays were detected by enzyme-linked immunosorbent assay (ELISA). The immunosuppressive abilities of Tregs

were evaluated by measuring their ability to inhibit the proliferation of effector cells. Results Higher proportions of Tregs were found in the CH and PNALT groups compared with the HS group. The populations of CD127 low/negative and CD45RA negative cells were higher in the CH group than in the PNALT group. The expressions of IL-10 and TGF-b in the CH and PNALT groups were significantly higher than those in the HS group. In addition, the immunosuppressive ability of Tregs from the CH group was increased relative to that in the PNALT and the HS group. Conclusions CHC patients, irrespective of liver function, had higher frequencies of Tregs than healthy subjects; however, only CHC patients with inflammation showed enhanced immunosuppressive function of Tregs. Keywords Hepatitis C Á Immunosuppression Á Regulatory T cells Abbreviations HCV Hepatitis C virus CHC Chronic hepatitis C ALT Alanine aminotransferase HCC Hepatocellular carcinoma NK Natural killer Treg Regulatory T cell Foxp3 Forkhead box P3 TGF Transforming growth factor IL-10 Interleukin-10

K.-C. Tseng Á Y.-H. Hsieh Á N.-S. Lai Department of Internal Medicine, Buddhist Dalin Tzu Chi General Hospital, Chia-Yi, Taiwan K.-C. Tseng Á Y.-H. Hsieh Á N.-S. Lai School of Medicine, Tzuchi University, Hualien, Taiwan Y.-C. Ho Á C. Li Á S.-F. Wu (&) Department of Life Science, Institute of Molecular Biology, National Chung-Cheng University, No. 168, University Rd., Min-Hsiung, Chia-Yi 62102, Taiwan e-mail: biosfw@ccu.edu.tw Z.-H. Wen Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan

Introduction Hepatitis C virus (HCV) is a small, enveloped, singlestranded, positive-sense RNA virus that belongs to the

123

J Gastroenterol

family flaviviridae and genus hepacivirus [1]. After HCV infection, the immune systems of 55–85% of infected patients cannot eliminate the virus, and in these cases, chronic hepatitis C (CHC) may develop [1]. Chronic hepatitis C is often asymptomatic, with persistently normal serum alanine aminotransferase (ALT) levels in 20–30% of patients, although it is usually associated with fluctuating or persistently elevated ALT levels [2, 3]. Major long-term complications of CHC include cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC) [1]. Retrospective and prospective studies on the long-term natural history of HCV infection have shown that 15–20% of CHC patients develop cirrhosis within 30 years [4]. Once cirrhosis occurs, the annual risk of HCC, hepatic decompensation, and liver-related death is approximately 1–4, 5, and 2–4%, respectively [4–7]. After HCV...

References: 1. Hoofnagle JH. Course and outcome of hepatitis C. Hepatology. 2002;36:S21–9. ´ 2. Marcellin P, Levy S, Erlinger S. Therapy of hepatitis C: patients with normal aminotransferase levels. Hepatology. 1997;26:S133–6. 3. Tassopoulos NC. Treatment of patients with chronic hepatitis C and normal ALT levels. J Hepatol. 1999;31(Suppl 1):193–6. 4. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001;345:41–52. 5. Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, Almasio P, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology. 1997;112:463–72. 6. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35–50. ˆ ` 7. Serfaty L, Aumaıtre H, Chazouilleres O, Bonnand AM, Rosmorduc O, Poupon RE, et al. Determinants of outcome of compensated hepatitis C virus-related cirrhosis. Hepatology. 1998;27:1435–40. 8. Golden-Mason L, Rosen HR. Natural killer cells: primary target for hepatitis C virus immune evasion strategies? Liver Transpl. 2006;12:363–72. 9. Diepolder HM. New insights into the immunopathogenesis of chronic hepatitis C. Antiviral Res. 2009;82:103–9. 10. Cramp ME, Carucci P, Rossol S, Chokshi S, Maertens G, Williams R, et al. Hepatitis C virus (HCV) specific immune responses in anti-HCV positive patients without hepatitis C viraemia. Gut. 1999;44:424–9. 11. Tsai SL, Liaw YF, Chen MH, Huang CY, Kuo GC. Detection of type 2-like T-helper cells in hepatitis C virus infection: implications for hepatitis C virus chronicity. Hepatology. 1997;25: 449–58. 12. Sakaguchi S. Naturally arising Foxp3-expressing CD25? CD4? regulatory T cells in immunological tolerance to self and nonself. Nat Immunol. 2005;6:345–52. 13. Belkaid Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol. 2007;7:875–88. 14. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4? CD25? regulatory T cells. Nat Immunol. 2003;4:330–6. 15. Alatrakchi N, Koziel M. Regulatory T cells and viral liver disease. J Viral Hepat. 2009;16:223–9. 16. Itose I, Kanto T, Kakita N, Takebe S, Inoue M, Higashitani K, et al. Enhanced ability of regulatory T cells in chronic hepatitis C patients with persistently normal alanine aminotransferase levels than those with active hepatitis. J Viral Hepat. 2009;16:844–52. 17. 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;38:1437–48. 18. Cabrera R, Tu Z, Xu Y, Firpi RJ, Rosen HR, Liu C, et al. An immunomodulatory role for CD4(?)CD25(?) regulatory T lymphocytes in hepatitis C virus infection. Hepatology. 2004;40: 1062–71. 19. Boettler T, Spangenberg HC, Neumann-Haefelin C, Panther E, Urbani S, Ferrari C, et al. 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; 79:7860–7. 20. Rushbrook SM, Ward SM, Unitt E, Vowler SL, Lucas M, Klenerman P, et al. Regulatory T cells suppress in vitro
123
J Gastroenterol proliferation of virus-specific CD8? T cells during persistent hepatitis C virus infection. J Virol. 2005;79:7852–9. Ebinuma H, Nakamoto N, Li Y, Price DA, Gostick E, Levine BL, et al. Identification and in vitro expansion of functional antigenspecific CD25? FoxP3? regulatory T cells in hepatitis C virus infection. J Virol. 2008;82:5043–53. Yoshizawa K, Abe H, Kubo Y, Kitahara T, Aizawa R, Matsuoka M, et al. Expansion of CD4(?)CD25(?)FoxP3(?) regulatory T cells in hepatitis C virus-related chronic hepatitis, cirrhosis and hepatocellular carcinoma. Hepatol Res. 2010;40:179–87. Bolacchi F, Sinistro A, Ciaprini C, Demin F, Capozzi M, Carducci FC, et al. 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;144:188–96. Lin CT, Yu MT, Li C, Ho YC, Shen CH, Liu DW, et al. Dysfunction of natural killer cells in patients with transitional cell carcinoma. Cancer Lett. 2010;291:39–45. Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H. Inhibition of CD4(?)25? T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood. 2005;105:2862–8. 26. Smyk-Pearson S, Golden-Mason L, Klarquist J, Burton JR Jr, Tester IA, Wang CC, et al. Functional suppression by FoxP3? CD4? CD25(high) regulatory T cells during acute hepatitis C virus infection. J Infect Dis. 2008;197:46–57. 27. Kanto T, Hayashi N. Immunopathogenesis of hepatitis C virus infection: multifaceted strategies subverting innate and adaptive immunity. Intern Med. 2006;45:183–91. 28. Bowen DG, Walker CM. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature. 2005;436:946–52. 29. Valmori D, Merlo A, Souleimanian NE, Hesdorffer CS, Ayyoub M. A peripheral circulating compartment of natural naive CD4 Tregs. J Clin Invest. 2005;115:1953–62. 30. Herman RB, Koziel MJ. Natural killer cells and hepatitis C: is losing inhibition the key to clearance? Clin Gastroenterol Hepatol. 2004;2:1061–3. 31. Thimme R, Lohmann V, Weber F. A target on the move: innate and adaptive immune escape strategies of hepatitis C virus. Antiviral Res. 2006;69:129–41. 32. Golden-Mason L, Madrigal-Estebas L, McGrath E, Conroy MJ, Ryan EJ, Hegarty JE, et al. Altered natural killer cell subset distributions in resolved and persistent hepatitis C virus infection following single source exposure. Gut. 2008;57:1121–8.
21.
22.
23.
24.
25.
123
Continue Reading

Please join StudyMode to read the full document

You May Also Find These Documents Helpful

  • Function of T Cells and B Cells Essay
  • Cytotoxic T cells Essay
  • T-Cells and Cd4 Essay
  • Cell Structure and Function Essay
  • Essay about Functions Of The Cells Autosaved
  • Structure and Function of Cells and Organelles Essay
  • Plant Cell Structure and Functions Essay
  • function and structure of four cells Essay

Become a StudyMode Member

Sign Up - It's Free