BCG 예방접종을 받은 개체에서 유도되어 있는 결핵균 균체항원에 특정한 CD8+T 세포의 보호 면역반응

M. tuberculosis Somatic Antigen Specific CD8+T cell Responses in BCG-Vaccinated Subjects

  • 조장은 (연세대학교 의과대학 미생물학교실) ;
  • 조상래 (연세대학교 의과대학 미생물학교실) ;
  • 이경화 (한림대학교 유전체응용연구소) ;
  • 박승규 (국립마산결핵병원) ;
  • 조성애 (연세대학교 의과대학 미생물학교실)
  • Cho, Jang-Eun (Department of Microbiology, Brain Korea 21 project for Medical Sciences, Yonsei University Medical Center) ;
  • Cho, Sang-Nae (Department of Microbiology, Brain Korea 21 project for Medical Sciences, Yonsei University Medical Center) ;
  • Lee, Kyung Wha (Hallym Institution for Genome Application Hallym University) ;
  • Park, Seung Kyu (National Masan Tuberculosis Hospital) ;
  • Cho, Sungae (Department of Microbiology, Brain Korea 21 project for Medical Sciences, Yonsei University Medical Center)
  • 투고 : 2005.06.16
  • 심사 : 2005.08.26
  • 발행 : 2005.09.30

초록

배 경 : 결핵의 보호면역 반응에서 CD8+T 세포에 의한 여러 기전이 중요한 역할을 한다는 사실이 최근에 보고되고 있다. $IFN-{\gamma}$ 분비 외에도 결핵균으로 감염된 세포에 독성을 나타내어 직접 결핵균으로 감염된 세포를 제거하는 독성능 또한 그 역할이 중요하다고 알려지고 있는데, BCG 예방접종을 받은 개체에서도 이러한 균체항원에 특정한 CD8+T 세포의 독성능이 유도되어 있어서 보호면역 반응에서의 역할을 하는지 연구하였다. 대상 및 방법 : HLA-A*0201 과 A*0206를 표현하며 BCG 예방접종을 한 개체들의 혈액에서 백혈구를 분리하고 균체항원의 항원결정기 ($ThyA_{30-38}$) 에 대한 독성능과 ex vivo $IFN-{\gamma}$ 분비능을 유도하였다. 결 과 : 이들 대상에게서 $IFN-{\gamma}$ 분비능과 독성능이 유도되는 것을 관찰할 수 있었고, 또한 HLA-A*0201에 결합하여 CD8+T 세포의 면역 반응을 일으키는 $ThyA_{30-38}$ 펩티드들은 HLA-A*0206인 개체에서도 면역반응을 일으키는 것을 관찰할 수 있었다. 결 론 : 균체 항원에 특정한 CD8+T 세포들의 $IFN-{\gamma}$ 분비 능과 독성능이 BCG 백신주사를 맞은 개체에서 유도되어 있는 것을 관찰할 수 있었다. 따라서 이러한 균체항원에 특정한 CD8+T 세포들이 보호면역 반응에 관여한다는 것을 제시하며, 또한 HLA-A*0201 개체들과 HLA-A*0206 개체들을 대상으로 하는 백신이나 치료제로써 $ThyA_{30-38}$ 펩티드의 사용 가능성을 제시한다.

Background : The immune responses mediated by CD8+T cells are known to be significant in controlling M. tuberculosis infections. In order to determine the role of cytotoxic CD8+T cells in the protective immune mechanism in latently infected subjects, this study examined whether or not the cytotoxic immune responses of CD8+T cells specific to the M. tuberculosis somatic antigens are induced in BCG vaccinated healthy subjects. Methods : Cytotoxicity and $IFN-{\gamma}$ elispot assays were used to investigate the activities of CD8+T cells specific for the $thyA_{30-38}$ peptide epitope in circulating peripheral blood mononuclear cells (PBMC) from BCG-vaccinated HLA-A*0201 and A*0206 subjects. Results : The results indicate the cytotoxic and $IFN-{\gamma}$ immune responses of CD8+T cells specific for $thyA_{30-38}$ were induced in BCG vaccinated healthy subjects. Conclusion : The cytotoxic and $IFN-{\gamma}$ responses by CD8+T cells specific for the M. tuberculosis somatic antigens are induced in BCG-vaccinated subjects, and appear to be involved in the protective immune mechanism in latently infected people against a M. tuberculosis infection.

키워드

참고문헌

  1. World Health Organization. WHO report on the tuberculosis epidermic. Publ. No. WHO/TB/95. Geneva: World Health Organization; 1995. p. 183
  2. Chan J, Flynn J. The immunological aspects of latency in tuberculosis. Clin Immunol 2004;110:2-12 https://doi.org/10.1016/S1521-6616(03)00210-9
  3. Flynn JL, Chan J. Immunology of tuberculosis. Annu Rev Immunol 2001;19:93-129 https://doi.org/10.1146/annurev.immunol.19.1.93
  4. Flynn JL. Immunology of tuberculosis and implications in vaccine development. Tuberculosis 2004;84:93-101 https://doi.org/10.1016/j.tube.2003.08.010
  5. Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med 1993;178:2249-54 https://doi.org/10.1084/jem.178.6.2249
  6. Flynn JL, Goldstein MM, Chan J, Triebold KJ, Pfeffer K, Lowenstein CJ, et al. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 1995; 2:561-72 https://doi.org/10.1016/1074-7613(95)90001-2
  7. Chan J, Tanaka K, Carroll D, Flynn J, Bloom BR. Effects of nitric oxide synthase inhibitors on murine infection with Mycobacterium tuberculosis. Infect Immun 1995;63:736-40
  8. Pathan AA, Wilkinson KA, Wilkinson RJ, Latif M, McShane H, Pasvol G, et al. High frequencies of circulating IFN-gamma-secreting CD8 cytotoxic T cells specific for a novel MHC class I-restricted Mycobacterium tuberculosis epitope in M. tuberculosis-infected subjects without disease. Eur J Immunol 2000;30: 2713-21 https://doi.org/10.1002/1521-4141(200009)30:9<2713::AID-IMMU2713>3.0.CO;2-4
  9. Smith SM, Brookes R, Klein MR, Malin AS, Lukey PT, King AS, et al. Human CD8+ CTL specific for the mycobacterial major secreted antigen 85A. J Immunol 2000;165:7088-95
  10. Lewinsohn DM, Alderson MR, Briden AL, Riddell SR, Reed SG, Grabstein KH, et al. Characterization of human CD8+ T cells reactive with Mycobacterium tuberculosis-infected antigen-presenting cells. J Exp Med 1998;187:1633-40 https://doi.org/10.1084/jem.187.10.1633
  11. Lewinsohn DM, Zhu L, Madison VJ, Dillon DC, Fling SP, Reed SG, et al. Classically restricted human CD8+ T lymphocytes derived from Mycobacterium tuber culosis-infected cells: definition of antigenic specificity. J Immunol 2001;166:439-46
  12. van Pinxteren LA, Cassidy JP, Smedegaard BH, Agger EM, Andersen P. Control of latent Mycobacterium tuberculosis infection is dependent on CD8 T cells. Eur J Immunol 2000;30:3689-98 https://doi.org/10.1002/1521-4141(200012)30:12<3689::AID-IMMU3689>3.0.CO;2-4
  13. Tully G, Kortsik C, Hohn H, Zehbe I, Hitzler WE, Neukirch C, et al. Highly focused T cell responses in latent human pulmonary Mycobacterium tuberculosis infection. J Immunol 2005;174:2174-84
  14. Canaday DH, Ziebold C, Noss EH, Chervenak KA, Harding CV, Boom WH. Activation of human CD8+ alpha beta TCR+ cells by Mycobacterium tuberculosis via an alternate class I MHC antigen-processing pathway. J Immunol 1999;162:372-9
  15. Cho S, Mehra V, Thoma-Uszynski S, Stenger S, Serbina N, Mazzaccaro RJ, et al. Antimicrobial activity of MHC class I-restricted CD8+ T cells in human tuberculosis. Proc Natl Acad Sci U S A 2000;97:12210-5
  16. Cho JE, Lee KW, Park SK, Cheon SH, Cho SN, Cho S. The study of MHC calss I restricted CD8+ T cell mediated immune responses against Mycobacterium tuberculosis infection: evidence of M. tuberculosis specific CD8+ T cells in TB patients and PPD+ healthy individuals. Immune Netw 2003;3:235-41
  17. Sette A, Vitiello A, Reherman B, Fowler P, Nayersina R, Kast WM, et al. The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. J Immunol 1994;153:5586-92
  18. del Guercio MF, Sidney J, Hermanson G, Perez C, Grey HM, Kubo RT, et al. Binding of a peptide antigen to multiple HLA alleles allows definition of an A2-like supertype. J Immunol 1995;154:685-93
  19. Hurely C. Sequence-based typing for HLA-A. In: Tilanus MG, Hansen JA, Hurley CK, editors. Calss I sequencing amplification of exons 2 and 3 based upon Cereb. IHWG Technical Manual. Vol. TM7A. Seatle: International Histocompatibility Working Group; 2000
  20. Murray PJ. Defining the requirements for immunological control of mycobacterial infections. Trends Microbiol 1999;7:366-72 https://doi.org/10.1016/S0966-842X(99)01567-X
  21. Flynn JL. Why is IFN-gamma insufficient to control tuberculosis? Trends Microbiol 1999;7:477-8
  22. Chen A, Wang L, Zhang J, Zou L, Jia Z, Zhou W, et al. H-2 Kd-restricted hepatitis B virus-derived epitope whose specific CD8+ T lymphocytes can produce gamma interferon without cytotoxicity. J Virol 2005;79:5568-76 https://doi.org/10.1128/JVI.79.9.5568-5576.2005
  23. Schnappinger D, Ehrt S, Voskuil MI, Liu Y, Mangan JA, Monahan IM, et al. Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: insights into the phagosomal environment. J Exp Med 2003;198:693-704 https://doi.org/10.1084/jem.20030846