Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1985 Dec 1;162(6):1745–1759. doi: 10.1084/jem.162.6.1745

Host resistance directed selectively against H-2-deficient lymphoma variants. Analysis of the mechanism

PMCID: PMC2187973  PMID: 3877776

Abstract

Three independent variants with a profound reduction of cell surface H- 2 have been selected from the C57BL/6 mouse-derived RBL-5 and EL-4 T lymphomas. After subcutaneous inoculation of low cell doses in syngeneic mice, the H-2- variants failed to grow out, whereas the H-2+ control lines showed progressive growth. No difference in growth rate or cloning efficiency was detectable in tissue culture. The in vivo difference in tumor outgrowth was analyzed in detail for one of the H-2- low lines. The outgrowth difference remained after the H-2-low variant and the control line had been injected subcutaneously in opposite flanks of the same mouse, and it was not dependent upon activity of mature T cells, since the same result was seen in athymic nude mice. The difference was partially sensitive to irradiation of the hosts. When mice were pretreated with anti-asialo GM1 antiserum, known to depress natural killer (NK) cell activity, the difference in outgrowth was abolished, and both the control line and the H-2- variant showed progressive growth in vivo. Experiments comparing the distribution and survival of isotope-prelabeled variant and wild type cells indicated that a rapid elimination of the former took place within 24 h after intravenous injection. These differences in tumor elimination were not seen in mice treated with anti-asialo GM1 antiserum. We conclude that the reduced tumorigenicity of sublines with impaired H-2 expression is largely, if not exclusively due to rapid elimination by NK cells. These findings may reflect an inverse, indirect relation between factors controlling H-2 expression and NK sensitivity. Another possible explanation is that major histocompatibility complex (MHC)-encoded gene products are directly involved in a regulatory signal in the NK cell system. According to this interpretation, immunological selectivity in the NK cell system would be achieved by the failure to recognize self- MHC, irrespective of the presence of foreign antigens, i.e. by detection of no-self rather than of nonself. This may also explain previous observations on H-2-linked hybrid resistance against lymphoid grafts and changes in H-2 phenotypes associated with tumor progression.

Full Text

The Full Text of this article is available as a PDF (1.0 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Becker S., Kiessling R., Lee N., Klein G. Modulation of sensitivity to natural killer cell lysis after in vitro explantation of a mouse lymphoma. J Natl Cancer Inst. 1978 Dec;61(6):1495–1498. [PubMed] [Google Scholar]
  2. Boon T. Antigenic tumor cell variants obtained with mutagens. Adv Cancer Res. 1983;39:121–151. doi: 10.1016/s0065-230x(08)61034-9. [DOI] [PubMed] [Google Scholar]
  3. Carlson G. A., Taylor B. A., Marshall S. T., Greenberg A. H. A genetic analysis of natural resistance to nonsyngeneic cells: the role of H-2. Immunogenetics. 1984;20(3):287–300. doi: 10.1007/BF00364210. [DOI] [PubMed] [Google Scholar]
  4. Carlson G. A., Wegmann T. G. Rapid in vivo destruction of semi-syngeneic and allogeneic cells by nonimmunized mice as a consequence of nonidentity at H-2. J Immunol. 1977 Jun;118(6):2130–2137. [PubMed] [Google Scholar]
  5. Cikes M., Friberg S., Jr, Klein G. Progressive loss of H-2 antigens with concomitant increase of cell-surface antigen(s) determined by Moloney leukemia virus in cultured murine lymphomas. J Natl Cancer Inst. 1973 Feb;50(2):347–362. doi: 10.1093/jnci/50.2.347. [DOI] [PubMed] [Google Scholar]
  6. Cudkowicz G., Bennett M. Peculiar immunobiology of bone marrow allografts. II. Rejection of parental grafts by resistant F 1 hybrid mice. J Exp Med. 1971 Dec 1;134(6):1513–1528. doi: 10.1084/jem.134.6.1513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cudkowicz G., Hochman P. S. Do natural killer cells engage in regulated reactions against self to ensure homeostasis? Immunol Rev. 1979;44:13–41. doi: 10.1111/j.1600-065x.1979.tb00266.x. [DOI] [PubMed] [Google Scholar]
  8. De Baetselier P., Katzav S., Gorelik E., Feldman M., Segal S. Differential expression of H-2 gene products in tumour cells in associated with their metastatogenic properties. Nature. 1980 Nov 13;288(5787):179–181. doi: 10.1038/288179a0. [DOI] [PubMed] [Google Scholar]
  9. Doherty P. C., Knowles B. B., Wettstein P. J. Immunological surveillance of tumors in the context of major histocompatibility complex restriction of T cell function. Adv Cancer Res. 1984;42:1–65. doi: 10.1016/s0065-230x(08)60455-8. [DOI] [PubMed] [Google Scholar]
  10. Eisenbach L., Segal S., Feldman M. MHC imbalance and metastatic spread in Lewis lung carcinoma clones. Int J Cancer. 1983 Jul 15;32(1):113–120. doi: 10.1002/ijc.2910320118. [DOI] [PubMed] [Google Scholar]
  11. Evans G. A., Margulies D. H., Shykind B., Seidman J. G., Ozato K. Exon shuffling: mapping polymorphic determinants on hybrid mouse transplantation antigens. Nature. 1982 Dec 23;300(5894):755–757. doi: 10.1038/300755a0. [DOI] [PubMed] [Google Scholar]
  12. Festenstein H., Schmidt W. Variation in MHC antigenic profiles of tumor cells and its biological effects. Immunol Rev. 1981;60:85–127. doi: 10.1111/j.1600-065x.1981.tb00363.x. [DOI] [PubMed] [Google Scholar]
  13. Frost P., Kerbel R. S., Bauer E., Tartamella-Biondo R., Cefalu W. Mutagen treatment as a means for selecting immunogenic variants from otherwise poorly immunogenic malignant murine tumors. Cancer Res. 1983 Jan;43(1):125–132. [PubMed] [Google Scholar]
  14. Gooding L. R. Characterization of a progressive tumor from C3H fibroblasts transformed in vitro with SV40 virus. Immunoresistance in vivo correlates with phenotypic loss of H-2Kk. J Immunol. 1982 Sep;129(3):1306–1312. [PubMed] [Google Scholar]
  15. Habu S., Fukui H., Shimamura K., Kasai M., Nagai Y., Okumura K., Tamaoki N. In vivo effects of anti-asialo GM1. I. Reduction of NK activity and enhancement of transplanted tumor growth in nude mice. J Immunol. 1981 Jul;127(1):34–38. [PubMed] [Google Scholar]
  16. Haywood G. R., McKhann C. F. Antigenic specificities on murine sarcoma cells. Reciprocal relationship between normal transplantation antigens (H-2) and tumor-specific immunogenicity. J Exp Med. 1971 Jun 1;133(6):1171–1187. doi: 10.1084/jem.133.6.1171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hofer K. G., Prensky W., Hughes W. L. Death and metastatic distribution of tumor cells in mice monitored with 125I-iododeoxy-uridine. J Natl Cancer Inst. 1969 Oct;43(4):763–773. [PubMed] [Google Scholar]
  18. Hui K., Grosveld F., Festenstein H. Rejection of transplantable AKR leukaemia cells following MHC DNA-mediated cell transformation. Nature. 1984 Oct 25;311(5988):750–752. doi: 10.1038/311750a0. [DOI] [PubMed] [Google Scholar]
  19. Hünig T., Bevan M. J. Specificity of cytotoxic T cells from athymic mice. J Exp Med. 1980 Sep 1;152(3):688–702. doi: 10.1084/jem.152.3.688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jones J. M., Feldman J. D. Alloantigen expression of a rat Moloney sarcoma. J Natl Cancer Inst. 1975 Oct;55(4):995–999. doi: 10.1093/jnci/55.4.995. [DOI] [PubMed] [Google Scholar]
  21. Katzav S., De Baetselier P., Tartakovsky B., Feldman M., Segal S. Alterations in major histocompatibility complex phenotypes of mouse cloned T10 sarcoma cells: association with shifts from nonmetastatic to metastatic cells. J Natl Cancer Inst. 1983 Aug;71(2):317–324. [PubMed] [Google Scholar]
  22. Klein G. O., Kärre K., Klein G., Kiessling R. The genetic regulation of NK-activity: studies on congenic mice with B10 or AKR background. J Immunogenet. 1980 Oct;7(5):401–407. doi: 10.1111/j.1744-313x.1980.tb00734.x. [DOI] [PubMed] [Google Scholar]
  23. Ozato K., Sachs D. H. Monoclonal antibodies to mouse MHC antigens. III. Hybridoma antibodies reacting to antigens of the H-2b haplotype reveal genetic control of isotype expression. J Immunol. 1981 Jan;126(1):317–321. [PubMed] [Google Scholar]
  24. Rolstad B., Ford W. L. The rapid elimination of allogeneic lymphocytes: relationship to established mechanisms of immunity and to lymphocyte traffic. Immunol Rev. 1983;73:87–113. doi: 10.1111/j.1600-065x.1983.tb01080.x. [DOI] [PubMed] [Google Scholar]
  25. SNELL G. D., STEVENS L. C. Histocompatibility genes of mice. III. H-1 and H-4, two histocompatibility loci in the first linkage group. Immunology. 1961 Oct;4:366–379. [PMC free article] [PubMed] [Google Scholar]
  26. Schrier P. I., Bernards R., Vaessen R. T., Houweling A., van der Eb A. J. Expression of class I major histocompatibility antigens switched off by highly oncogenic adenovirus 12 in transformed rat cells. 1983 Oct 27-Nov 2Nature. 305(5937):771–775. doi: 10.1038/305771a0. [DOI] [PubMed] [Google Scholar]
  27. Warner N. L., Woodruff M. F., Burton R. C. Inhibition of the growth of lymphoid tumours in syngeneic athymic (nude) mice. Int J Cancer. 1977 Jul 15;20(1):146–155. doi: 10.1002/ijc.2910200122. [DOI] [PubMed] [Google Scholar]
  28. Wortis H. H. Immunological studies of nude mice. Contemp Top Immunobiol. 1974;3:243–263. doi: 10.1007/978-1-4684-3045-5_10. [DOI] [PubMed] [Google Scholar]
  29. Zuniga M. C., Malissen B., McMillan M., Brayton P. R., Clark S. S., Forman J., Hood L. Expression and function of transplantation antigens with altered or deleted cytoplasmic domains. Cell. 1983 Sep;34(2):535–544. doi: 10.1016/0092-8674(83)90386-0. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES