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. 1986 Sep 1;164(3):723–738. doi: 10.1084/jem.164.3.723

Cooperation between cytotoxic and helper T lymphocytes in protection against lethal Sendai virus infection. Protection by T cells is MHC- restricted and MHC-regulated; a model for MHC-disease associations

PMCID: PMC2188381  PMID: 3018121

Abstract

The in vivo importance of class I MHC regulation of the Tc response to a natural pathogenic agent of high virulence was studied on the basis of our previous demonstration of a major difference in the capacity to generate a Sendai virus-specific Tc response between C57BL/6 (B6, H-2b) mice and H-2Kb mutant B6.C-H-2bm1 (bm 1) mice. These two mouse strains differ from each other only in three amino acids in the crucial H-2Kb restriction element for this response. bm 1 mice, in contrast to B6 mice, are Tc nonresponders against this virus, but show Sendai-specific T cell proliferation, antibody production, and DTH reactions, as well as NK cell activity, equal to those of B6 mice. B6, Sendai Tc-deficient bm 1 and T cell-deficient B6 nu/nu mice differ from each other in susceptibility to lethal pneumonia induced by i.n. inoculation of virulent Sendai virus. The lethal dose (LD50) in B6 mice averaged 152 TCID50, in bm 1 mice, 14 TCID50 and in B6 nu/nu mice 0.5 TCID50. The importance of Tc was also shown by the complete protection of B6 nu/nu mice against infection with a lethal virus dose by i.v. injection of a Sendai virus-specific, IL-2-dependent and H-2Kb-restricted B6 Tc clone. In vivo protection by this Tc clone was H-2Kb-restricted. Apart from Tc, an important role for virus-specific Th cells is evident from the difference in susceptibility between bm 1 and B6 nu/nu mice. This conclusion was supported by the demonstration that the mean survival time of B6 nu/nu and bm 1 nu/nu mice could be significantly prolonged, in an I-Ab-restricted manner, by the injection of in vitro-propagated, Sendai-specific B6 or bm 1 Th clones after a lethal dose of Sendai virus, and by the demonstration that inoculation of these Th clones provided help to virus-specific Tc by means of IL-2 production. Strikingly, Th and Tc cooperate in anti-Sendai virus immunity, since permanent survival of lethally infected nu/nu mice was only achieved by inoculation of a mixture of Tc and Th clones or a mixture of a Tc clone and rIL-2. This study provides a unique model for the study of MHC- disease associations.

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Selected References

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  1. Allan J. E., Doherty P. C. Immune T cells can protect or induce fatal neurological disease in murine lymphocytic choriomeningitis. Cell Immunol. 1985 Feb;90(2):401–407. doi: 10.1016/0008-8749(85)90204-7. [DOI] [PubMed] [Google Scholar]
  2. Brenan M., Müllbacher A. Analysis of H-2 determinants recognized during the induction of H-Y-immune cytotoxic T cells by monoclonal antibodies in vitro. J Exp Med. 1981 Aug 1;154(2):563–568. doi: 10.1084/jem.154.2.563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Byrne J. A., Oldstone M. B. Biology of cloned cytotoxic T lymphocytes specific for lymphocytic choriomeningitis virus: clearance of virus in vivo. J Virol. 1984 Sep;51(3):682–686. doi: 10.1128/jvi.51.3.682-686.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cantor H., Boyse E. A. Functional subclasses of T lymphocytes bearing different Ly antigens. II. Cooperation between subclasses of Ly+ cells in the generation of killer activity. J Exp Med. 1975 Jun 1;141(6):1390–1399. doi: 10.1084/jem.141.6.1390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Collins M. J., Jr, Parker J. C. Murine virus contaminants of leukemia viruses and transplantable tumors. J Natl Cancer Inst. 1972 Oct;49(4):1139–1143. [PubMed] [Google Scholar]
  6. Debré P., Boyer B., Gisselbrecht S., Bismuth A., Lévy J. P. Genetic control of sensitivity to Moloney leukemia virus in mice. III. The three H-2 linked Rmv genes are immune response genes controlling the antiviral antibody response. Eur J Immunol. 1980 Dec;10(12):914–918. doi: 10.1002/eji.1830101205. [DOI] [PubMed] [Google Scholar]
  7. Doherty P. C., Dunlop M. B., Parish C. R., Zinkernagel R. M. Inflammatory process in murine lymphocytic choriomeningitis is maximal in H-2K or H-2D compatible interactions. J Immunol. 1976 Jul;117(1):187–190. [PubMed] [Google Scholar]
  8. Doherty P. C., Zinernagel R. M. Capacity of sensitized thymus-derived lymphocytes to induce fatal lymphocytic choriomeningitis is restricted by the H-2 gene complex. J Immunol. 1975 Jan;114(1 Pt 1):30–33. [PubMed] [Google Scholar]
  9. Finberg R., Benacerraf B. Induction, control and consequences of virus specific cytotoxic T cells. Immunol Rev. 1981;58:157–180. doi: 10.1111/j.1600-065x.1981.tb00353.x. [DOI] [PubMed] [Google Scholar]
  10. Gomard E., Hénin Y., Colombani M. J., Lévy J. P. Immune response genes control T killer cell response against Moloney tumor antigen cytolysis regulating reactions against the best available H-2 + viral antigen association. J Exp Med. 1980 Jun 1;151(6):1468–1476. doi: 10.1084/jem.151.6.1468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kast W. M., de Waal L. P., Melief C. J. Thymus dictates major histocompatibility complex (MHC) specificity and immune response gene phenotype of class II MHC-restricted T cells but not of class I MHC-restricted T cells. J Exp Med. 1984 Dec 1;160(6):1752–1766. doi: 10.1084/jem.160.6.1752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lehmann-Grube F., Assmann U., Löliger C., Moskophidis D., Löhler J. Mechanism of recovery from acute virus infection. I. Role of T lymphocytes in the clearance of lymphocytic choriomeningitis virus from spleens of mice. J Immunol. 1985 Jan;134(1):608–615. [PubMed] [Google Scholar]
  13. Lin Y. L., Askonas B. A. Biological properties of an influenza A virus-specific killer T cell clone. Inhibition of virus replication in vivo and induction of delayed-type hypersensitivity reactions. J Exp Med. 1981 Aug 1;154(2):225–234. doi: 10.1084/jem.154.2.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lukacher A. E., Braciale V. L., Braciale T. J. In vivo effector function of influenza virus-specific cytotoxic T lymphocyte clones is highly specific. J Exp Med. 1984 Sep 1;160(3):814–826. doi: 10.1084/jem.160.3.814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. McIntyre K. R., Seidman J. G. Nucleotide sequence of mutant I-A beta bm12 gene is evidence for genetic exchange between mouse immune response genes. Nature. 1984 Apr 5;308(5959):551–553. doi: 10.1038/308551a0. [DOI] [PubMed] [Google Scholar]
  16. Melief C. J., Stukart M. J., de Waal L. P., Kast W. M., Melvold R. W. Specificity and regulation of cytotoxic T-lymphocyte responses analyzed with H-2 mutants. Transplant Proc. 1983 Dec;15(4):2086–2089. [PubMed] [Google Scholar]
  17. Melief C. J., van der Meulen M. Y., Christiaans B. J., de Greeve P. Cooperation between subclass of T lymphocytes in the in vitro generation of cytotoxicity against a mutant H-2K difference. An analysis with anti-Lyt antisera. Eur J Immunol. 1979 Jan;9(1):7–12. doi: 10.1002/eji.1830090103. [DOI] [PubMed] [Google Scholar]
  18. Melino M. R., Epstein S. L., Sachs D. H., Hansen T. H. Idiotypic and fluorometric analysis of the antibodies that distinguish the lesion of the I-A mutant B6.C-H-2bm12. J Immunol. 1983 Jul;131(1):359–364. [PubMed] [Google Scholar]
  19. Nairn R., Yamaga K., Nathenson S. G. Biochemistry of the gene products from murine MHC mutants. Annu Rev Genet. 1980;14:241–277. doi: 10.1146/annurev.ge.14.120180.001325. [DOI] [PubMed] [Google Scholar]
  20. Oldstone M. B., Ahmed R., Byrne J., Buchmeier M. J., Riviere Y., Southern P. Virus and immune responses: lymphocytic choriomeningitis virus as a prototype model of viral pathogenesis. Br Med Bull. 1985 Jan;41(1):70–74. doi: 10.1093/oxfordjournals.bmb.a072029. [DOI] [PubMed] [Google Scholar]
  21. Parker J. C., Whiteman M. D., Richter C. B. Susceptibility of inbred and outbred mouse strains to Sendai virus and prevalence of infection in laboratory rodents. Infect Immun. 1978 Jan;19(1):123–130. doi: 10.1128/iai.19.1.123-130.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pease L. R., Schulze D. H., Pfaffenbach G. M., Nathenson S. G. Spontaneous H-2 mutants provide evidence that a copy mechanism analogous to gene conversion generates polymorphism in the major histocompatibility complex. Proc Natl Acad Sci U S A. 1983 Jan;80(1):242–246. doi: 10.1073/pnas.80.1.242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pfizenmaier K., Pan S. H., Knowles B. B. Preferential H-2 association in cytotoxic T cell responses to SV40 tumor-associated specific antigens. J Immunol. 1980 Apr;124(4):1888–1891. [PubMed] [Google Scholar]
  24. Rosenthal K. L., Zinkernagel R. M. Inability of mice to generate cytotoxic T lymphocytes to vesicular stomatitis virus restricted to H-2Kk or H-2Dk. J Immunol. 1981 Feb;126(2):446–451. [PubMed] [Google Scholar]
  25. Schreier M. H., Tees R., Nordin A. A., Benner R., Bianchi A. T., van Zwieten M. J. Functional aspects of helper T cell clones. Immunobiology. 1982 Mar;161(1-2):107–138. doi: 10.1016/S0171-2985(82)80021-1. [DOI] [PubMed] [Google Scholar]
  26. Sethi K. K., Omata Y., Schneweis K. E. Protection of mice from fatal herpes simplex virus type 1 infection by adoptive transfer of cloned virus-specific and H-2-restricted cytotoxic T lymphocytes. J Gen Virol. 1983 Feb;64(Pt 2):443–447. doi: 10.1099/0022-1317-64-2-443. [DOI] [PubMed] [Google Scholar]
  27. Simpson E., Matsunaga T. Physiological function of major histocompatibility complex macromolecules. Facts and hypotheses. Transplantation. 1979 May;27(5):295–297. doi: 10.1097/00007890-197905000-00001. [DOI] [PubMed] [Google Scholar]
  28. Taylor P. M., Askonas B. A. Diversity in the biological properties of anti-influenza cytotoxic T cell clones. Eur J Immunol. 1983 Sep;13(9):707–711. doi: 10.1002/eji.1830130904. [DOI] [PubMed] [Google Scholar]
  29. Vlug A., Schoenmakers H. J., Melief C. J. Genes of the H-2 complex regulate the antibody response to murine leukemia virus. J Immunol. 1981 Jun;126(6):2355–2360. [PubMed] [Google Scholar]
  30. Vlug A., Zijlstra M., de Goede R. E., Hesselink W. G., Schoenmakers H. J., Melief C. J. H-2 control of the cytotoxic antibody response against a newly defined MuLV-related cell-surface antigen: G(B10.A). Int J Cancer. 1983 May 15;31(5):617–626. doi: 10.1002/ijc.2910310514. [DOI] [PubMed] [Google Scholar]
  31. Zijlstra M., de Goede R. E., Schoenmakers H., Radaszkiewicz T., Melief C. J. Ecotropic and dualtropic mink cell focus-inducing murine leukemia viruses can induce a wide spectrum of H-2 controlled lymphoma types. Virology. 1984 Oct 30;138(2):198–211. doi: 10.1016/0042-6822(84)90345-3. [DOI] [PubMed] [Google Scholar]
  32. Zinkernagel R. M., Althage A., Cooper S., Kreeb G., Klein P. A., Sefton B., Flaherty L., Stimpfling J., Shreffler D., Klein J. Ir-genes in H-2 regulate generation of anti-viral cytotoxic T cells. Mapping to K or D and dominance of unresponsiveness. J Exp Med. 1978 Aug 1;148(2):592–606. doi: 10.1084/jem.148.2.592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Zinkernagel R. M., Callahan G. N. Low responsiveness to Dk or Db plus vaccinia virus or to Kk plus lymphocytic choriomeningitis virus assessed by availability of D or K products. Tissue Antigens. 1981 May;17(5):507–517. doi: 10.1111/j.1399-0039.1981.tb00738.x. [DOI] [PubMed] [Google Scholar]
  34. Zinkernagel R. M., Doherty P. C. MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv Immunol. 1979;27:51–177. doi: 10.1016/s0065-2776(08)60262-x. [DOI] [PubMed] [Google Scholar]
  35. Zinkernagel R. M., Pfau C. J., Hengartner H., Althage A. Susceptibility to murine lymphocytic choriomeningitis maps to class I MHC genes--a model for MHC/disease associations. 1985 Aug 29-Sep 4Nature. 316(6031):814–817. doi: 10.1038/316814a0. [DOI] [PubMed] [Google Scholar]
  36. de Waal L. P., Kast W. M., Melvold R. W., Melief C. J. Regulation of the cytotoxic T lymphocyte response against Sendai virus analyzed with H-2 mutants. J Immunol. 1983 Mar;130(3):1090–1096. [PubMed] [Google Scholar]
  37. von Boehmer H., Haas W. H-2 restricted cytolytic and noncytolytic T cell clones: isolation, specificity and functional analysis. Immunol Rev. 1981;54:27–56. doi: 10.1111/j.1600-065x.1981.tb00433.x. [DOI] [PubMed] [Google Scholar]

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