IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

Relationship between Poor Immunogenicity of HLA-A2-Restricted Peptide Epitopes and Paucity of Naïve $CD8^+$ T-Cell Precursors in HLA-A2-Transgenic Mice

  • Choi, Yoon Seok (Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST) ;
  • Lee, Dong Ho (Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST) ;
  • Shin, Eui-Cheol (Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST)
  • Received : 2014.07.08
  • Accepted : 2014.08.01
  • Published : 2014.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

We examined the immunogenicity of H-2 class I-restricted and HLA-A2-restricted epitopes through peptide immunization of HLA-A2-transgenic mice that also express mouse H-2 class I molecules. All four of the tested epitopes restricted by H-2 class I robustly elicited T-cell responses, but four of seven epitopes restricted by HLA-A2 did not induce T-cell responses, showing that HLA-A2-restricted peptide epitopes tend to be poorly immunogenic in HLA-A2-transgenic mice. This finding was confirmed in HLA-A2-transgenic mice infected with a recombinant vaccinia virus expressing hepatitis C virus proteins. We examined the precursor frequency of epitope-specific naïve $CD8^+$ T cells in HLA-A2-transgenic and conventional C57BL/6 mice and found that the poor immunogenicity of HLA-A2-restricted peptide epitopes is related to the paucity of naïve $CD8^+$ T-cell precursors in HLA-A2-transgenic mice. These results provide direction for the improvement of mouse models to study epitope repertoires and the immunodominance of human T-cell responses.

Keywords

References

  1. Spits, H. 2002. Development of alphabeta T cells in the human thymus. Nat. Rev. Immunol. 2: 760-772. https://doi.org/10.1038/nri913
  2. Barry, M., and R. C. Bleackley. 2002. Cytotoxic T lymphocytes: all roads lead to death. Nat. Rev. Immunol. 2: 401-409.
  3. Yewdell, J. W., and J. R. Bennink. 1999. Immunodominance in major histocompatibility complex class I-restricted T lymphocyte responses. Ann. Rev. Immunol. 17: 51-88. https://doi.org/10.1146/annurev.immunol.17.1.51
  4. Jenkins, M. K., and J. J. Moon. 2012. The role of naive T cell precursor frequency and recruitment in dictating immune response magnitude. J. Immunol. 188: 4135-4140. https://doi.org/10.4049/jimmunol.1102661
  5. Kotturi, M. F., I. Scott, T. Wolfe, B. Peters, J. Sidney, H. Cheroutre, M. G. von Herrath, M. J. Buchmeier, H. Grey, and A. Sette. 2008. Naive precursor frequencies and MHC binding rather than the degree of epitope diversity shape $CD8^+$ T cell immunodominance. J. Immunol. 181: 2124-2133. https://doi.org/10.4049/jimmunol.181.3.2124
  6. Obar, J. J., K. M. Khanna, and L. Lefrancois. 2008. Endogenous naive $CD8^+$ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28: 859-869. https://doi.org/10.1016/j.immuni.2008.04.010
  7. Epstein, H., R. Hardy, J. S. May, M. H. Johnson, and N. Holmes. 1989. Expression and function of HLA-A2.1 in transgenic mice. Eur. J. Immunol. 19: 1575-1583. https://doi.org/10.1002/eji.1830190909
  8. Le, A. X., E. J. Bernhard, M. J. Holterman, S. Strub, P. Parham, E. Lacy, and V. H. Engelhard. 1989. Cytotoxic T cell responses in HLA-A2.1 transgenic mice. Recognition of HLA alloantigens and utilization of HLA-A2.1 as a restriction element. J. Immunol. 142: 1366-1371.
  9. Vitiello, A., D. Marchesini, J. Furze, L. A. Sherman, and R. W. Chesnut. 1991. Analysis of the HLA-restricted influenza-specific cytotoxic T lymphocyte response in transgenic mice carrying a chimeric human-mouse class I major histocompatibility complex. J. Exp. Med. 173: 1007-1015. https://doi.org/10.1084/jem.173.4.1007
  10. Nickerson, C. L., J. Hanson, and C. S. David. 1990. Expression of HLA-B27 in transgenic mice is dependent on the mouse H-2D genes. J. Exp. Med. 172: 1255-1261. https://doi.org/10.1084/jem.172.4.1255
  11. Alexander, J., C. Oseroff, J. Sidney, P. Wentworth, E. Keogh, G. Hermanson, F. V. Chisari, R. T. Kubo, H. M. Grey, and A. Sette. 1997. Derivation of HLA-A11/Kb transgenic mice: functional CTL repertoire and recognition of human A11-restricted CTL epitopes. J. Immunol. 159: 4753-4761.
  12. Alexander, J., C. Oseroff, J. Sidney, and A. Sette. 2003. Derivation of HLA-B*0702 transgenic mice: functional CTL repertoire and recognition of human B*0702-restricted CTL epitopes. Hum. Immunol. 64: 211-223. https://doi.org/10.1016/S0198-8859(02)00786-3
  13. Pascolo, S., N. Bervas, J. M. Ure, A. G. Smith, F. A. Lemonnier, and B. Perarnau. 1997. HLA-A2.1-restricted education and cytolytic activity of CD8(+) T lymphocytes from beta2 microglobulin (beta2m) HLA-A2.1 monochain transgenic H-2Db beta2m double knockout mice. J. Exp. Med. 185: 2043-2051. https://doi.org/10.1084/jem.185.12.2043
  14. Firat, H., F. Garcia-Pons, S. Tourdot, S. Pascolo, A. Scardino, Z. Garcia, M. L. Michel, R. W. Jack, G. Jung, K. Kosmatopoulos, L. Mateo, A. Suhrbier, F. A. Lemonnier, and P. Langlade-Demoyen. 1999. H-2 class I knockout, HLAA2.1-transgenic mice: a versatile animal model for preclinical evaluation of antitumor immunotherapeutic strategies. Eur. J. Immunol. 29: 3112-3121. https://doi.org/10.1002/(SICI)1521-4141(199910)29:10<3112::AID-IMMU3112>3.0.CO;2-Q
  15. Firat, H., M. Cochet, P. S. Rohrlich, F. Garcia-Pons, S. Darche, O. Danos, F. A. Lemonnier, and P. Langlade-Demoyen. 2002. Comparative analysis of the CD8(+) T cell repertoires of H-2 class I wild-type/HLA-A2.1 and H-2 class I knockout/HLA-A2.1 transgenic mice. Int. Immunol. 14: 925-934. https://doi.org/10.1093/intimm/dxf056
  16. Newberg, M. H., D. H. Smith, S. B. Haertel, D. R. Vining, E. Lacy, and V. H. Engelhard. 1996. Importance of MHC class 1 alpha2 and alpha3 domains in the recognition of self and non-self MHC molecules. J. Immunol. 156: 2473-2480.
  17. Martin, S., B. Ortmann, U. Pflugfelder, U. Birsner, and H. U. Weltzien. 1992. Role of hapten-anchoring peptides in defining hapten-epitopes for MHC-restricted cytotoxic T cells. Cross-reactive TNP-determinants on different peptides. J. Immunol. 149: 2569-2575.
  18. Kim, S. K., M. Cornberg, X. Z. Wang, H. D. Chen, L. K. Selin, and R. M. Welsh. 2005. Private specificities of CD8 T cell responses control patterns of heterologous immunity. J. Exp. Med. 201: 523-533. https://doi.org/10.1084/jem.20041337
  19. Trobaugh, D. W., L. Yang, F. A. Ennis, and S. Green. 2010. Altered effector functions of virus-specific and virus cross-reactive $CD8^+$ T cells in mice immunized with related flaviviruses. Eur. J. Immunol. 40: 1315-1327. https://doi.org/10.1002/eji.200839108
  20. Clute, S. C., L. B. Watkin, M. Cornberg, Y. N. Naumov, J. L. Sullivan, K. Luzuriaga, R. M. Welsh, and L. K. Selin. 2005. Cross-reactive influenza virus-specific $CD8^+$ T cells contribute to lymphoproliferation in Epstein-Barr virus-associated infectious mononucleosis. J. Clin. Invest. 115: 3602-3612. https://doi.org/10.1172/JCI25078
  21. Wedemeyer, H., E. Mizukoshi, A. R. Davis, J. R. Bennink, and B. Rehermann. 2001. Cross-reactivity between hepatitis C virus and Influenza A virus determinant-specific cytotoxic T cells. J. Virol. 75: 11392-11400. https://doi.org/10.1128/JVI.75.23.11392-11400.2001
  22. Wedemeyer, H., X. S. He, M. Nascimbeni, A. R. Davis, H. B. Greenberg, J. H. Hoofnagle, T. J. Liang, H. Alter, and B. Rehermann. 2002. Impaired effector function of hepatitis C virus-specific $CD8^+$ T cells in chronic hepatitis C virus infection. J. Immunol. 169: 3447-3458. https://doi.org/10.4049/jimmunol.169.6.3447
  23. Thimme, R., D. Oldach, K. M. Chang, C. Steiger, S. C. Ray, and F. V. Chisari. 2001. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J. Exp. Med. 194: 1395-1406. https://doi.org/10.1084/jem.194.10.1395
  24. Wentworth, P. A., A. Vitiello, J. Sidney, E. Keogh, R. W. Chesnut, H. Grey, and A. Sette. 1996. Differences and similarities in the A2.1-restricted cytotoxic T cell repertoire in humans and human leukocyte antigen-transgenic mice. Eur. J. Immunol. 26: 97-101. https://doi.org/10.1002/eji.1830260115
  25. Wedemeyer, H., S. Gagneten, A. Davis, R. Bartenschlager, S. Feinstone, and B. Rehermann. 2001. Oral immunization with HCV-NS3-transformed Salmonella: induction of HCV-specific CTL in a transgenic mouse model. Gastroenterology 121: 1158-1166. https://doi.org/10.1053/gast.2001.29311
  26. Lee, D. H., S. H. Kim, W. Kang, Y. S. Choi, S. H. Lee, S. R. Lee, S. You, H. K. Lee, K. T. Chang, and E. C. Shin. 2011. Adjuvant effect of bacterial outer membrane vesicles with penta-acylated lipopolysaccharide on antigen-specific T cell priming. Vaccine 29: 8293-8301. https://doi.org/10.1016/j.vaccine.2011.08.102
  27. Moon, J. J., H. H. Chu, M. Pepper, S. J. McSorley, S. C. Jameson, R. M. Kedl, and M. K. Jenkins. 2007. Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 27: 203-213. https://doi.org/10.1016/j.immuni.2007.07.007
  28. Altmann, D. M., D. C. Douek, A. J. Frater, C. M. Hetherington, H. Inoko, and J. I. Elliott. 1995. The T cell response of HLA-DR transgenic mice to human myelin basic protein and other antigens in the presence and absence of human CD4. J. Exp. Med. 181: 867-875. https://doi.org/10.1084/jem.181.3.867
  29. Nabozny, G. H., J. M. Baisch, S. Cheng, D. Cosgrove, M. M. Griffiths, H. S. Luthra, and C. S. David. 1996. HLA-DQ8 transgenic mice are highly susceptible to collagen-induced arthritis: a novel model for human polyarthritis. J. Exp. Med. 183: 27-37. https://doi.org/10.1084/jem.183.1.27
  30. Rosloniec, E. F., D. D. Brand, L. K. Myers, Y. Esaki, K. B. Whittington, D. M. Zaller, A. Woods, J. M. Stuart, and A. H. Kang. 1998. Induction of autoimmune arthritis in HLA-DR4 (DRB1*0401) transgenic mice by immunization with human and bovine type II collagen. J. Immunol. 160: 2573-2578.
  31. Mix, H., C. Weiler-Normann, R. Thimme, G. Ahlenstiel, E. C. Shin, J. Herkel, C. S. David, A. W. Lohse, and B. Rehermann. 2008. Identification of CD4 T-cell epitopes in soluble liver antigen/liver pancreas autoantigen in autoimmune hepatitis. Gastroenterology 135: 2107-2118. https://doi.org/10.1053/j.gastro.2008.07.029
  32. Li, L. P., J. C. Lampert, X. Chen, C. Leitao, J. Popovic, W. Muller, and T. Blankenstein. 2010. Transgenic mice with a diverse human T cell antigen receptor repertoire. Nat. Med. 16: 1029-1034. https://doi.org/10.1038/nm.2197

Cited by

  1. Development of a SFTSV DNA vaccine that confers complete protection against lethal infection in ferrets vol.10, pp.1, 2014, https://doi.org/10.1038/s41467-019-11815-4