Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1988 Nov 1;168(5):1781–1800. doi: 10.1084/jem.168.5.1781

Molecular characterization of the C3HfB/HeN H-2Kkm2 mutation. Implications for the molecular basis of alloreactivity

PMCID: PMC2189124  PMID: 2903213

Abstract

The C3HfB/HeN (C3Hf) mouse strain expresses an H-2Kk molecule, previously denoted H-2Kkv1, that is structurally and functionally distinct from H-2Kk of the parental C3H strain. By molecular genetic analysis, we demonstrate that the C3Hf H-2K gene carries a homozygous coding region mutation relative to the C3H allele, revealing that C3Hf meets the requirements for assignment of a mutant haplotype, H-2km2. C3Hf H-2Kkm2 bears a single clustered substitution of four nucleotides within 14 contiguous nucleotides in exon 3. Since this sequence also is present intact at the homologous position in H-2Dk of both C3H and C3Hf, the origin of the H-2Kkm2 mutation is consistent with a nonreciprocal sequence transfer from the H-2Dk donor gene, analogous to the mechanism proposed for generation of the H-2Kb mutations. The H- 2Kkm2 mutation encodes three clustered amino acid substitutions, at positions 95, 98, and 99, that map to one of the large beta strands at the bottom of the peptide antigen binding cleft of the H-2Kkm2 molecule. The nature and location of these amino acid substitutions are unique relative to any other known H-2 mutant or HLA variant, and underscore the importance of the beta-pleated sheet in influencing CTL recognition. These results indicate that H-2Kkm2 alloantigenicity may derive largely from altered presentation of self cellular peptides.

Full Text

The Full Text of this article is available as a PDF (1.4 MB).

Selected References

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

  1. Allen P. M., Matsueda G. R., Evans R. J., Dunbar J. B., Jr, Marshall G. R., Unanue E. R. Identification of the T-cell and Ia contact residues of a T-cell antigenic epitope. 1987 Jun 25-Jul 1Nature. 327(6124):713–715. doi: 10.1038/327713a0. [DOI] [PubMed] [Google Scholar]
  2. Archibald A. L., Thompson N. A., Kvist S. A single nucleotide difference at the 3' end of an intron causes differential splicing of two histocompatibility genes. EMBO J. 1986 May;5(5):957–965. doi: 10.1002/j.1460-2075.1986.tb04309.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arnold B., Burgert H. G., Archibald A. L., Kvist S. Complete nucleotide sequence of the murine H-2Kk gene. Comparison of three H-2K locus alleles. Nucleic Acids Res. 1984 Dec 21;12(24):9473–9487. doi: 10.1093/nar/12.24.9473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berzofsky J. A. Structural features of protein antigenic sites recognized by helper T cells: what makes a site immunodominant? Year Immunol. 1986;2:28–38. [PubMed] [Google Scholar]
  5. Bjorkman P. J., Saper M. A., Samraoui B., Bennett W. S., Strominger J. L., Wiley D. C. Structure of the human class I histocompatibility antigen, HLA-A2. Nature. 1987 Oct 8;329(6139):506–512. doi: 10.1038/329506a0. [DOI] [PubMed] [Google Scholar]
  6. Bjorkman P. J., Saper M. A., Samraoui B., Bennett W. S., Strominger J. L., Wiley D. C. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature. 1987 Oct 8;329(6139):512–518. doi: 10.1038/329512a0. [DOI] [PubMed] [Google Scholar]
  7. Callahan G. N., Walker L. E., Martin W. J. Biochemical comparison of H-2K antigen isolated from C3HfB/HeN and C3H/HeN mice. Immunogenetics. 1981 Mar 1;12(5-6):561–568. doi: 10.1007/BF01561696. [DOI] [PubMed] [Google Scholar]
  8. Chen E. Y., Seeburg P. H. Supercoil sequencing: a fast and simple method for sequencing plasmid DNA. DNA. 1985 Apr;4(2):165–170. doi: 10.1089/dna.1985.4.165. [DOI] [PubMed] [Google Scholar]
  9. Chen Y. T., Obata Y., Stockert E., Takahashi T., Old L. J. Tla-region genes and their products. Immunol Res. 1987;6(1-2):30–45. doi: 10.1007/BF02918102. [DOI] [PubMed] [Google Scholar]
  10. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  11. Claverie J. M., Kourilsky P. The peptidic self model: a reassessment of the role of the major histocompatibility complex molecules in the restriction of the T-cell response. Ann Inst Pasteur Immunol. 1986 Nov-Dec;137D(3):425–442. [PubMed] [Google Scholar]
  12. Clayberger C., Parham P., Rothbard J., Ludwig D. S., Schoolnik G. K., Krensky A. M. HLA-A2 peptides can regulate cytolysis by human allogeneic T lymphocytes. Nature. 1987 Dec 24;330(6150):763–765. doi: 10.1038/330763a0. [DOI] [PubMed] [Google Scholar]
  13. Egorov I. K., Egorov O. S. Detection of new MHC mutations in mice by skin grafting, tumor transplantation and monoclonal antibodies: a comparison. Genetics. 1988 Feb;118(2):287–298. doi: 10.1093/genetics/118.2.287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  15. Gipson T. G., Imamura M., Conliffe M. A., Martin W. J. Lung tumor-associated derepressed alloantigen coded for by the K region of the H-2 major histocompatibility complex. J Exp Med. 1978 May 1;147(5):1363–1373. doi: 10.1084/jem.147.5.1363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hood L., Steinmetz M., Malissen B. Genes of the major histocompatibility complex of the mouse. Annu Rev Immunol. 1983;1:529–568. doi: 10.1146/annurev.iy.01.040183.002525. [DOI] [PubMed] [Google Scholar]
  17. Imamura M., Gipson T. G., Bensky N., Justice R., Martin W. J. Lung tumor-reactive cytotoxic lymphocytes generated in mixed lymphocyte reaction between C3HfeB/HeN (H-2kb) and C3H/HeN (H-2k) strain mice. J Immunol. 1979 May;122(5):1863–1866. [PubMed] [Google Scholar]
  18. Imamura M., Martin W. J. Variation in expression of H-2 histocompatibility antigens on tumor cells. Transplant Proc. 1980 Mar;12(1):77–79. [PubMed] [Google Scholar]
  19. Jaulin C., Perrin A., Abastado J. P., Dumas B., Papamatheakis J., Kourilsky P. Polymorphism in mouse and human class I H-2 and HLA genes is not the result of random independent point mutations. Immunogenetics. 1985;22(5):453–470. doi: 10.1007/BF00418091. [DOI] [PubMed] [Google Scholar]
  20. Klein J., Figueroa F. Evolution of the major histocompatibility complex. Crit Rev Immunol. 1986;6(4):295–386. [PubMed] [Google Scholar]
  21. Kourilsky P., Chaouat G., Rabourdin-Combe C., Claverie J. M. Working principles in the immune system implied by the "peptidic self" model. Proc Natl Acad Sci U S A. 1987 May;84(10):3400–3404. doi: 10.1073/pnas.84.10.3400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lemke H., Hämmerling G. J., Hämmerling U. Fine specificity analysis with monoclonal antibodies of antigens controlled by the major histocompatibility complex and by the Qa/TL region in mice. Immunol Rev. 1979;47:175–206. doi: 10.1111/j.1600-065x.1979.tb00293.x. [DOI] [PubMed] [Google Scholar]
  23. Linsk R., Vogel J., Stauss H., Forman J., Goodenow R. S. Structure and function of three novel MHC class I antigens derived from a C3H ultraviolet-induced fibrosarcoma. J Exp Med. 1986 Sep 1;164(3):794–813. doi: 10.1084/jem.164.3.794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Martin W. J., Gipson T. G., Conliffe M. A., Cotton W. G., Dove L. F., Rice J. M. Histocompatibility difference between C3HfeB/HeN and C3H/HeN mice: tumour induced in C3HfeB/HeN mice expresses C3H/HeN-associated alloantigen. J Immunogenet. 1978 Aug;5(4):255–260. doi: 10.1111/j.1744-313x.1978.tb00653.x. [DOI] [PubMed] [Google Scholar]
  25. Martin W. J., Gipson T. G., Martin S. E., Rice J. M. Derepressed alloantigen in transplacentally induced lung tumor coded for by H-2 linked gene. Science. 1976 Oct 29;194(4264):532–533. doi: 10.1126/science.973137. [DOI] [PubMed] [Google Scholar]
  26. Martin W. J., Gipson T. G., Rice J. M. H-2a-associated alloantigen expressed by several transplacentally-induced lung tumours of C3Hf mice. Nature. 1977 Feb 24;265(5596):738–739. doi: 10.1038/265738a0. [DOI] [PubMed] [Google Scholar]
  27. Martinko J. M., Solheim J. C., Geliebter J. The H-2Kkml mutation: nucleotide sequence and comparative analysis. Mol Immunol. 1987 Feb;24(2):197–200. doi: 10.1016/0161-5890(87)90092-7. [DOI] [PubMed] [Google Scholar]
  28. Maryanski J. L., Pala P., Corradin G., Jordan B. R., Cerottini J. C. H-2-restricted cytolytic T cells specific for HLA can recognize a synthetic HLA peptide. Nature. 1986 Dec 11;324(6097):578–579. doi: 10.1038/324578a0. [DOI] [PubMed] [Google Scholar]
  29. McMillan M., Lewis K. D., Rovner D. M. Molecular characterization of novel H-2 class I molecules expressed by a C3H UV-induced fibrosarcoma. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5485–5489. doi: 10.1073/pnas.82.16.5485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mellor A. L., Weiss E. H., Ramachandran K., Flavell R. A. A potential donor gene for the bm1 gene conversion event in the C57BL mouse. Nature. 1983 Dec 22;306(5945):792–795. doi: 10.1038/306792a0. [DOI] [PubMed] [Google Scholar]
  31. Minamide L. S., Callahan G. N., Grosveld F. G., Hui K. M. The nucleotide sequence of the H-2K gene of C3Hf/HeN mice. Immunogenetics. 1988;27(2):148–152. doi: 10.1007/BF00351091. [DOI] [PubMed] [Google Scholar]
  32. Myers R. M., Larin Z., Maniatis T. Detection of single base substitutions by ribonuclease cleavage at mismatches in RNA:DNA duplexes. Science. 1985 Dec 13;230(4731):1242–1246. doi: 10.1126/science.4071043. [DOI] [PubMed] [Google Scholar]
  33. Nathenson S. G., Geliebter J., Pfaffenbach G. M., Zeff R. A. Murine major histocompatibility complex class-I mutants: molecular analysis and structure-function implications. Annu Rev Immunol. 1986;4:471–502. doi: 10.1146/annurev.iy.04.040186.002351. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. Schulze D. H., Pease L. R., Geier S. S., Reyes A. A., Sarmiento L. A., Wallace R. B., Nathenson S. G. Comparison of the cloned H-2Kbm1 variant gene with the H-2Kb gene shows a cluster of seven nucleotide differences. Proc Natl Acad Sci U S A. 1983 Apr;80(7):2007–2011. doi: 10.1073/pnas.80.7.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sheil J. M., Bevan M. J., Lefrancois L. Characterization of dual-reactive H-2Kb-restricted anti-vesicular stomatitus virus and alloreactive cytotoxic T cells. J Immunol. 1987 Jun 1;138(11):3654–3660. [PubMed] [Google Scholar]
  37. Song E. S., Linsk R., Olson C. A., McMillan M., Goodenow R. S. Allospecific cytotoxic T lymphocytes recognize an H-2 peptide in the context of a murine major histocompatibility complex class I molecule. Proc Natl Acad Sci U S A. 1988 Mar;85(6):1927–1931. doi: 10.1073/pnas.85.6.1927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Stauss H. J., Linsk R., Fischer A., Watts S., Banasiak D., Haberman A., Clark I., Forman J., McMillan M., Schreiber H. Isolation of the MHC genes encoding the tumour-specific class I antigens expressed on a murine fibrosarcoma. J Immunogenet. 1986 Apr-Jun;13(2-3):101–111. doi: 10.1111/j.1744-313x.1986.tb01090.x. [DOI] [PubMed] [Google Scholar]
  39. Townsend A. R., Rothbard J., Gotch F. M., Bahadur G., Wraith D., McMichael A. J. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell. 1986 Mar 28;44(6):959–968. doi: 10.1016/0092-8674(86)90019-x. [DOI] [PubMed] [Google Scholar]
  40. Treisman R., Orkin S. H., Maniatis T. Structural and functional defects in beta-thalassemia. Prog Clin Biol Res. 1983;134:99–121. [PubMed] [Google Scholar]
  41. Watts S., Vogel J. M., Harriman W. D., Itoh T., Stauss H. J., Goodenow R. S. DNA sequence analysis of the C3H H-2Kk and H-2Dk loci. Evolutionary relationships to H-2 genes from four other mouse strains. J Immunol. 1987 Dec 1;139(11):3878–3885. [PubMed] [Google Scholar]
  42. Weiss E. H., Mellor A., Golden L., Fahrner K., Simpson E., Hurst J., Flavell R. A. The structure of a mutant H-2 gene suggests that the generation of polymorphism in H-2 genes may occur by gene conversion-like events. Nature. 1983 Feb 24;301(5902):671–674. doi: 10.1038/301671a0. [DOI] [PubMed] [Google Scholar]
  43. Weiss E. H. Molecular biology of the mouse Q region. Immunol Res. 1987;6(3):179–191. doi: 10.1007/BF02918090. [DOI] [PubMed] [Google Scholar]
  44. 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]

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

RESOURCES