DOI QR코드

DOI QR Code

만성 바이러스 감염에서 면역조절인자 FoxP3, PD-1 및 CTLA-4의 역할

The Roles of Immune Regulatory Factors FoxP3, PD-1, and CTLA-4 in Chronic Viral Infection

  • 조효선 (덕성여자대학교 약학대학 약학과)
  • Cho, Hyosun (Department of Pharmacy, Duksung Women's University)
  • 투고 : 2013.07.29
  • 심사 : 2013.09.25
  • 발행 : 2013.09.30

초록

인간면역결핍바이러스(Human immunodeficiency virus; HIV), B형 간염 바이러스(Hepatitis B virus; HBV), 그리고 C형 간염 바이러스(Hepatitis C virus; HCV)는 만성 감염질환을 일으키는 대표적인 바이러스들이다. 인체내 감염시 임상적 진행경과에 따른 바이러스 특이 T림프구의 항바이러스 기능변화 및 바이러스의 체내 지속성과 T림프구에 발현되는 다양한 면역인자(e.g., CD28, CD25, FoxP3, PD-1, CTLA-4)들과의 구체적인 상관관계는 최근 많은 국내외 연구진들을 통해 연구되고 있다. 그 중 FoxP3 (forkhead box P3), PD-1 (programmed death-1) 그리고 CTLA-4 (cytotoxic T lymphocyte-associated antigen 4)는 T림프구에서 발현되는 면역조절인자로 만성 바이러스성 감염시 그 발현이 증가되는 것으로 관찰되었으며, 항바이러스 작용을 가지는 T림프구의 기능결핍과 밀접한 상관관계가 있는 것으로 알려져 있다. 본 총설에서는 만성적인 HIV, HBV, 그리고 HCV 감염에서 바이러스 특이 T림프구에서 발현되는 FoxP3, PD1, 그리고 CTLA-4의 발현변화와 각 질환의 임상적 진행경과와의 상관성, 그리고 이들 발현이 T림프구의 항바이러스 기능에 미치는 영향 등을 중심으로 기술하였다.

Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) cause viral infections that lead to chronic diseases. When they invade human body, virus specific T cells play an important role in antiviral effector functions including killing virus-infected cells and helping B cells to produce specific antibodies against viral proteins. The antiviral activity of T cells is usually affected by immune-regulatory factors that express on surface of T cells. Recently, many researchers have investigated the relationship between effector functions of virus specific T cells and characteristics of immune regulatory factors (e.g., CD28, CD25, CD45RO, FoxP3, PD-1, CTLA-4). In particular, Immune inhibitory molecules such as forkhead box P3 (FoxP3), programmed death-1 (PD-1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are associated with T-cell dysfunction. They are shown to be up-regulated in chronic viral diseases such as hepatitis B, hepatitis C or human immunodeficiency virus infection. Therefore, the positive correlation between viral persistence and expression of immune regulatory factors (FoxP3, PD-1, and CTLA-4) has been suggested. In this review, the roles of immune regulatory factors FoxP3, PD-1, and CTLA-4 were discussed in chronic viral diseases such as HIV, HBV, or HCV.

키워드

참고문헌

  1. Alvarez, D. 2004. Clinical perspective: Battling hepatitis C in our HIV-infected patients. Res. Initiat. Treat. Action 10, 26-27.
  2. Azuma, T., Takahashi, T., Kunisato, A., Kitamura, T., and Hirai, H. 2003. Human CD4+ CD25+ regulatory T cells suppress NKT cell functions. Cancer Res. 63, 4516–4520.
  3. Barber, D.L., Wherry, E.J., Masopust, D., Zhu, B., Allison, J.P., Sharpe, A.H., Freeman, G.J., and Ahmed, R. 2006. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687. https://doi.org/10.1038/nature04444
  4. Bertoletti, A. and Naoumov, N.V. 2003. Translation of immunological knowledge into better treatments of chronic hepatitis B. J. Hepatol. 39, 115-124. https://doi.org/10.1016/S0168-8278(03)00126-0
  5. Billerbeck, E., Bottler, T., and Thimme, R. 2007. Regulatory T cells in viral hepatitis. World J. Gastroenterol. 13, 4858-4864. https://doi.org/10.3748/wjg.v13.i36.4858
  6. Boulassel, M.R., Delwart, M.R., and Sepulveda, H. 2006. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 12, 1198-1202. https://doi.org/10.1038/nm1482
  7. Brunkow, M.E., Jeffery, E.W., Hjerrild, K.A., Paeper, B., Clark, L.B., Yasayko, S.A., Wilkinson, J.E., Galas, D., Ziegler, S.F., and Ramsdell, F. 2001. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68-73.
  8. Cao, J., Zhang, L., Huang, S., Chen, P., Zou, L., Chen, H., Xiang, Y., Lai, X., and Ren, G. 2011. Aberrant production of soluble co-stimulatory molecules CTLA-4 and CD28 in patients with chronic hepatitis B. Microb. Pathog. 51, 262-267. https://doi.org/10.1016/j.micpath.2011.06.003
  9. Card, C.M., McLaren, P.J., Wachihi, C., Kimani, J., Plummer, F.A., and Fowke, K.R. 2009. Decreased immune activation in resistance to HIV-1 infection is associated with an elevated frequency of CD4(+)CD25(+)FOXP3(+) regulatory T cells. J. Infect. Dis. 199, 1318-1322. https://doi.org/10.1086/597801
  10. Chae, H.B., Kim, J.H., Kim, J.K., and Yim, H.J. 2009, Current status of liver diseases in Korea: hepatitis B. Korean J. Hepatol. 15, S13-24. https://doi.org/10.3350/kjhep.2009.15.S6.S13
  11. Chen, L. 2004. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat. Rev. Immunol. 4, 336-347. https://doi.org/10.1038/nri1349
  12. Chen, Y.Q. and Shi, H.Z. 2006. CD28/CTLA-4--CD80/CD86 and ICOS--B7RP-1 costimulatory pathway in bronchial asthma. Allergy 61, 15–26.
  13. Day, C.L., Kaufmann, D.E., Kiepiela, P., Brown, J.A., Moodley, E.S., Reddy, S., Mackey, E.W., Miller, J.D., Leslie, A.J., and DePierres, C. 2006. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354. https://doi.org/10.1038/nature05115
  14. Ebinuma, H., Nakamoto, N., Li, Y., Price, D.A., Gostick, E., Levine, B.L., Tobias, J., Kwok, W.W., and Chang, K.M. 2008. Identification and in vitro expansion of functional antigen-specific CD25+ FoxP3+ regulatory T cells in hepatitis C virus infection. J. Virol. 82, 5043-5053. https://doi.org/10.1128/JVI.01548-07
  15. Evans, A., Riva, A., Cooksley, H., Phillips, S., Puranik, S., Nathwani, A., Brett, S., Chokshi, S., and Naoumov, N.V. 2008. Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e-antigen seroconversion. Hepatology 48, 759–769. https://doi.org/10.1002/hep.22419
  16. Fife, B.T. and Bluestone, J.A. 2008. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol. Rev. 224, 166-182. https://doi.org/10.1111/j.1600-065X.2008.00662.x
  17. Freeman, G.J., Wherry, E.J., Ahmed, R., and Sharpe, A.H. 2006. Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J. Exp. Med. 203, 2223-2227. https://doi.org/10.1084/jem.20061800
  18. Gardiner, D., Lalezari, J., Lawitz, E., DiMicco, M., Ghalib, R., Reddy, K.R., Chang, K.M., Sulkowski, M., Marro, S.O., Anderson, J., and et al. 2013. A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection. PLoS One 22, 8(5):e63818. https://doi.org/10.1371/journal.pone.0063818
  19. Golden-Mason, L., Palmer, B., Klarquist, J., Mengshol, J.A., and Castelblanco, N. 2007. Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus-specific CD8+ T cells associated with reversible immune dysfunction. J. Virol. 81, 9249-9258. https://doi.org/10.1128/JVI.00409-07
  20. Kahn, J.O. and Walker, B.D. 1998. Acute human immunodeficiency virus type 1 infection. N. Engl. J. Med. 331, 33-39.
  21. Kim, Y.S., Pai, C.H., Chi, H.S., Kim, D.W., Min, Y.I., and Ahn, Y.O. 1992. Prevalence of hepatitis C virus antibody among Korean adults. J. Korean Med. Sci. 7, 333-336. https://doi.org/10.3346/jkms.1992.7.4.333
  22. Lauer, G.M. and Walker, B.D. 2001. Hepatitis C virus infection. New Engl. J. Med. 345, 41-52. https://doi.org/10.1056/NEJM200107053450107
  23. Lee, C.K., Han, K.H., Suh, J.H., Cho, Y.S., Won, S.Y., Chon, C.Y., Moon, Y.M., and Park, I.S. 2005. HBV-specific CD8+ T cells for sustained HBeAg seroconversion after lamivudine therapy. Korean J. Hepatol. 11, 34-42.
  24. Lee, K.S. and Kim, D.J. 2012. Korean association for the study of the liver. Clin. Mol. Hepatol. 2, 109-162.
  25. Liang, T.J., Rehermann, B., Seeff, L.B., and Hoofnagle, J.H. 2000. Pathogenesis, natural istory, treatment and prevention of hepatitis C. Ann. Intern. Med. 32, 296-305.
  26. Li, S., Gowans, E.J., Chougnet, C., Plebanski, M., and Dittmer, U. 2008. Natural regulatory T cells and persistent viral infection. J. Virol. 82, 21-30. https://doi.org/10.1128/JVI.01768-07
  27. Linsley, P.S., Greene, J.L., Tan, P., Bradshaw, J., Ledbetter, J.A., Anasetti, C., and Damle, N.K. 1992. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J. Exp. Med. 176, 1595-1604. https://doi.org/10.1084/jem.176.6.1595
  28. Lim, H.W., Hillsamer, P., Banham, A.H., and Kim, C.H. 2005. Cutting edge: direct suppression of B cells by CD4+CD25+ regulatory T cells. J. Immunol. 175, 4180-4183. https://doi.org/10.4049/jimmunol.175.7.4180
  29. McHutchison, J.G., Gordon, S.C., Schiff, E.R., Shiffman, M.L., Lee, W.M., Rustigi, V.K., Goodman, Z.D., Ling, M.H., Cort, S., and Albrect, J.K. 1998. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N. Eng. J. Med. 339, 1485-1492. https://doi.org/10.1056/NEJM199811193392101
  30. Mills, K.H. and McGuirk, P. 2004. Antigen-specific regulatory T cells - their induction and role in infection. Semin. Immunol. 16, 107-117. https://doi.org/10.1016/j.smim.2003.12.006
  31. Muhlbauer, M., Fleck, M., Schutz, C., Weiss, T., Froh, M., Blank, C., Schölmerich, J., and Hellerbrand, C. 2006. PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis. J. Hepatol. 45, 520-528. https://doi.org/10.1016/j.jhep.2006.05.007
  32. Nakamoto, N., Cho, H., Shaked, A., Olthoff, K., Valiga, M.E., Kaminski, M., Gostick, E., Price, D.A., Freeman, G.J., Wherry, E.J., and et al. 2009. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog. 5, e1000313. https://doi.org/10.1371/journal.ppat.1000313
  33. Nakamoto, N., Kaplan, D.E., Coleclough, J., Li, Y., Valiga, M.E., Kaminski, M., Shaked, A., Olthoff, K., Gostick, E., Price, D.A., and et al. 2008. Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization. Gastroenterology 134, 1927–1937. https://doi.org/10.1053/j.gastro.2008.02.033
  34. Ohkura, N. and Sakaguchi, S. 2010. Regulatory T cells: roles of T cell receptor for their development and function. Semin Immunopathol. 32, 95–106. https://doi.org/10.1007/s00281-010-0200-5
  35. Oh, M.D. and Choe, K.W. 1999. Epidemiology of HIV infection in the republic of Korea. J. Korean Med. Sci. 14, 469-474. https://doi.org/10.3346/jkms.1999.14.5.469
  36. Operskalski, E.A. and Kovacs, A. 2011, HIV/HCV co-infection: Pathogenesis, clinical complications, treatment, and new therapeutic technologies. Curr. HIV/AIDS Rep. 8, 12-22. https://doi.org/10.1007/s11904-010-0071-3
  37. Pagliaro, L., Craxi, A., Cammaa, C., Tine, F., Di Marco, V., and Almasio, P. 1994. Interferon-alpha for chronic hepatitis C: an analysis of pretreatment clinical predictors of response. Hepatology 19, 820–828.
  38. Palella, F.J., Delaney, K.M., Moorman, A.C., Loveless, M.O., Fuhrer, J., Satten, G.A., Aschman, D.J., and Holmberg, S.D. 1998. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N. Engl. J. Med. 338, 853-860. https://doi.org/10.1056/NEJM199803263381301
  39. Peng, G., Li, S., Wu, W., Tan, X., Chen, Y., and Chen, Z. 2008. PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients. Mol. Immunol. 45, 963-970. https://doi.org/10.1016/j.molimm.2007.07.038
  40. Probst-Kepper, M., Balling, R., and Buer, J. 2010. FOXP3: required but not sufficient. the role of GARP (LRRC32) as a safeguard of the regulatory phenotype. Curr. Mol. Med. 10, 533-539.
  41. Romagnani, C., Della Chiesa, M., Kohler, S., Moewes, B., Radbruch, A., Moretta, L., Moretta, A., and Thiel, A. 2005. Activation of human NK cells by plasmacytoid dendritic cells and its modulation by CD4+ T helper cells and CD4+CD25hi T regulatory cells. Eur. J. Immunol. 35, 2452-2458. https://doi.org/10.1002/eji.200526069
  42. Rouse, B.T., Sarangi, P.P., and Suvas, S. 2006. Regulatory T cells in virus infections. Immunol. Rev. 212, 272-286. https://doi.org/10.1111/j.0105-2896.2006.00412.x
  43. Sakaguchi, S. 2005. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and nonself. Nat. Immunol. 6, 345-352. https://doi.org/10.1038/ni1178
  44. Sheppard, K.A., Fitz, L.J., Lee, J.M., Benander, C., George, J.A., Wooters, J., Qiu, Y., Jussif, J.M., Carter, L.L., Wood, C.R., and Chaudhary, D. 2004. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 3, 37–41.
  45. Stamper, C.C., Zhang, Y., Tobin, J.F., Erbe, D.V., Ikemizu, S., Davis, S.J., Stahl, M.L., Seehra, J., Somers, W.S., and Mosyak, L. 2001, Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses. Nature, 410, 608–611. https://doi.org/10.1038/35069118
  46. Stoop, J.N., Baan, C.C., van der Laan, L.J., Kuipers, E.J., Kusters, J.G., and Janssen, H.L. 2005. Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology 41, 771–777. https://doi.org/10.1002/hep.20649
  47. Suchard, M.S., Mayne, E., Green, V.A., Shalekoff, S., Donninger, S.L., Stevens, W.S., Gray, C.M., and Tiemessen, C.T. 2010. FOXP3 expression is upregulated in CD4T cells in progressive HIV-1 infection and is a marker of disease severity. PLoS One 5, e11762. https://doi.org/10.1371/journal.pone.0011762
  48. Teoh, N.C. and and Farrell, G.C. 2004. Management of chronic hepatitis C virus infection: a new era of disease conrol. Intern. Med. J. 34, 324-337. https://doi.org/10.1111/j.1445-5994.2004.00615.x
  49. Tone, Y., Furuuchi, K., Kojima, Y., Tykocinski, M.L., Greene, M.I., and Tone, M. 2008. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat. Immunol. 9, 194-202. https://doi.org/10.1038/ni1549
  50. Trautmann, L., Janbazian, L., Chomont, N., Said, E.A., Wang, G., Gimmig, S., Bessette, B., Boulassel, M.R., Delwart, E., Sepulveda, H., and et al. 2006. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 12, 1198-1202. https://doi.org/10.1038/nm1482
  51. Leng, Q., Bentwich, Z., Magen, E., Kalinkovich, A., and Borkow, G. 2002. CTLA-4 upregulation during HIV infection: association with anergy and possible target for therapeutic intervention. AIDS 16, 519–529. https://doi.org/10.1097/00002030-200203080-00002
  52. Trzonkowski, P., Szmit, E., Mysliwska, J., Dobyszuk, A., and Mysliwski, A. 2004. CD4+CD25+ T regulatory cells inhibit cytotoxic activity of T CD8+ and NK lymphocytes in the direct cell-to-cell interaction. Clin. Immunol. 112, 258-267. https://doi.org/10.1016/j.clim.2004.04.003
  53. Vigouroux, S., Yvon, E., Biagi, E., and Brenner, M.K. 2004. Antigen-induced regulatory T cells. Blood 104, 26–33. https://doi.org/10.1182/blood-2004-01-0182
  54. Wan, Y.Y. 2010. Regulatory T cells: immune suppression and beyond. Cell Mol. Immunol. 7, 204-210. https://doi.org/10.1038/cmi.2010.20
  55. Wenjin, Z., Chuanhui, P., Yunle, W., Lateef, S.A., and Shusen, Z. 2012. Longitudinal fluctuations in PD1 and PD-L1 expression in association with changes in anti-viral immune response in chronic hepatitis B. BMC Gastroenterol. 12, 109–115. https://doi.org/10.1186/1471-230X-12-109
  56. Yim, H.J. and Lok, A.S. 2006. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology 43, S173–181. https://doi.org/10.1002/hep.21006
  57. Zaunders, J.J., Munier, M.L., Kaufmann, D.E., Suzuki, K., Brereton, C., Sasson, S.C., Seddiki, N., Koelsch, K., and Landay, A. 2006. Infection of CD127_(interleukin-7 receptor_) CD4_ cells and overexpression of CTLA-4 are linked to loss of antigen-specific CD4 T cells during primary human immunodeficiency virus type 1 infection. J. Virol. 80, 10162-10172. https://doi.org/10.1128/JVI.00249-06