Abstract
The UV-induced, C3H fibrosarcoma, 1591, expresses at least three unique MHC class I antigens not found on normal C3H tissue. Here we report the complete DNA sequence of the three novel class I genes encoding these molecules, and describe in detail the recognition of the individual products by tumor-reactive and allospecific CTL. Remarkably, although C3H does not appear to express H-2L locus information, this C3H tumor expresses two distinct antigens, termed A149 and A166, which are extremely homologous to each other and to the H-2Ld antigen from BALB/c. The gene encoding the third novel class I antigen from 1591, A216, is quite homologous to H-2Kk) throughout its 3' end. Since all three of these genes account for polymorphic restriction fragments not found in C3H, it is likely that they were derived by recombination from the endogenous class I genes of C3H. The DNA sequence homology of A149, A166, and H-2Ld is especially significant given the functional conservation observed between the products of these genes. Limited sequence substitutions appear to correlate with some of the discrete serological differences observed between these molecules. In addition, both A149 and A166 crossreact, but to differing extents, with H-2Ld at the level of T cell recognition. Our results are consistent with the view that CTL recognize complex conformational determinants on class I molecules, but extend previous observations by comparing a set of antigens with discrete and overlapping structural and functional differences.
Full Text
The Full Text of this article is available as a PDF (1.2 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Allen H., Wraith D., Pala P., Askonas B., Flavell R. A. Domain interactions of H-2 class I antigens alter cytotoxic T-cell recognition sites. Nature. 1984 May 17;309(5965):279–281. doi: 10.1038/309279a0. [DOI] [PubMed] [Google Scholar]
- 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]
- Arnold B., Horstmann U., Kuon W., Burgert H. G., Hämmerling G. J., Kvist S. Alloreactive cytolytic T-cell clones preferentially recognize conformational determinants on histocompatibility antigens: analysis with genetically engineered hybrid antigens. Proc Natl Acad Sci U S A. 1985 Oct;82(20):7030–7034. doi: 10.1073/pnas.82.20.7030. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bluestone J. A., Foo M., Allen H., Segal D., Flavell R. A. Allospecific cytolytic T lymphocytes recognize conformational determinants on hybrid mouse transplantation antigens. J Exp Med. 1985 Jul 1;162(1):268–281. doi: 10.1084/jem.162.1.268. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clark S. S., Geier S., Nathenson S. G., Forman J. Analysis of associative recognition determinants on class I H-2Kb mutant molecules. Immunogenetics. 1985;22(4):391–397. doi: 10.1007/BF00430922. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Fisher M. S., Kripke M. L. Systemic alteration induced in mice by ultraviolet light irradiation and its relationship to ultraviolet carcinogenesis. Proc Natl Acad Sci U S A. 1977 Apr;74(4):1688–1692. doi: 10.1073/pnas.74.4.1688. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Flood P. M., Kripke M. L., Rowley D. A., Schreiber H. Suppression of tumor rejection by autologous anti-idiotypic immunity. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2209–2213. doi: 10.1073/pnas.77.4.2209. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Forman J., Goodenow R. S., Hood L., Ciavarra R. Use of DNA-mediated gene transfer to analyze the role of H-2Ld in controlling the specificity of anti-vesicular stomatitis virus cytotoxic T cells. J Exp Med. 1983 Apr 1;157(4):1261–1272. doi: 10.1084/jem.157.4.1261. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goodenow R. S., Vogel J. M., Linsk R. L. Histocompatibility antigens on murine tumors. Science. 1985 Nov 15;230(4727):777–783. doi: 10.1126/science.2997918. [DOI] [PubMed] [Google Scholar]
- Kripke M. L. Immunologic mechanisms in UV radiation carcinogenesis. Adv Cancer Res. 1981;34:69–106. doi: 10.1016/s0065-230x(08)60239-0. [DOI] [PubMed] [Google Scholar]
- Kripke M. L. Latency, histology, and antigenicity of tumors induced by ultraviolet light in three inbred mouse strains. Cancer Res. 1977 May;37(5):1395–1400. [PubMed] [Google Scholar]
- Kripke M. L., Lofgreen J. S., Beard J., Jessup J. M., Fisher M. S. In vivo immune responses of mice during carcinogenesis by ultraviolet irradiation. J Natl Cancer Inst. 1977 Oct;59(4):1227–1230. doi: 10.1093/jnci/59.4.1227. [DOI] [PubMed] [Google Scholar]
- Kvist S., Roberts L., Dobberstein B. Mouse histocompatibility genes: structure and organisation of a Kd gene. EMBO J. 1983;2(2):245–254. doi: 10.1002/j.1460-2075.1983.tb01413.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Miyazaki J., Appella E., Zhao H., Forman J., Ozato K. Expression and function of a nonglycosylated major histocompatibility class I antigen. J Exp Med. 1986 Apr 1;163(4):856–871. doi: 10.1084/jem.163.4.856. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moore K. W., Sher B. T., Sun Y. H., Eakle K. A., Hood L. DNA sequence of a gene encoding a BALB/c mouse Ld transplantation antigen. Science. 1982 Feb 5;215(4533):679–682. doi: 10.1126/science.7058332. [DOI] [PubMed] [Google Scholar]
- Murre C., Choi E., Weis J., Seidman J. G., Ozato K., Liu L., Burakoff S. J., Reiss C. S. Dissection of serological and cytolytic T lymphocyte epitopes on murine major histocompatibility antigens by a recombinant H-2 gene separating the first two external domains. J Exp Med. 1984 Jul 1;160(1):167–178. doi: 10.1084/jem.160.1.167. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ozato K., Hansen T. H., Sachs D. H. Monoclonal antibodies to mouse MHC antigens. II. Antibodies to the H-2Ld antigen, the products of a third polymorphic locus of the mouse major histocompatibility complex. J Immunol. 1980 Dec;125(6):2473–2477. [PubMed] [Google Scholar]
- Ozato K., Takahashi H., Appella E., Sears D. W., Murre C., Seidman J. G., Kimura S., Tada N. Polymorphism of murine major histocompatibility Class I antigen: assignment of putative allodeterminants to distinct positions of the amino acid sequence within the first external domain of the antigen. J Immunol. 1985 Mar;134(3):1749–1758. [PubMed] [Google Scholar]
- Philipps C., McMillan M., Flood P. M., Murphy D. B., Forman J., Lancki D., Womack J. E., Goodenow R. S., Schreiber H. Identification of a unique tumor-specific antigen as a novel class I major histocompatibility molecule. Proc Natl Acad Sci U S A. 1985 Aug;82(15):5140–5144. doi: 10.1073/pnas.82.15.5140. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reiss C. S., Evans G. A., Margulies D. H., Seidman J. G., Burakoff S. J. Allospecific and virus-specific cytolytic T lymphocytes are restricted to the N or C1 domain of H-2 antigens expressed on L cells after DNA-mediated gene transfer. Proc Natl Acad Sci U S A. 1983 May;80(9):2709–2712. doi: 10.1073/pnas.80.9.2709. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reyes A. A., Schöld M., Wallace R. B. The complete amino acid sequence of the murine transplantation antigen H-2Db as deduced by molecular cloning. Immunogenetics. 1982;16(1):1–9. doi: 10.1007/BF00364437. [DOI] [PubMed] [Google Scholar]
- Roberts L. K. Characterization of a cloned ultraviolet radiation (UV)-induced suppressor T cell line that is capable of inhibiting anti-UV tumor-immune responses. J Immunol. 1986 Mar 1;136(5):1908–1916. [PubMed] [Google Scholar]
- Roberts L. K., Daynes R. A. Modification of the immunogenic properties of chemically induced tumors arising in hosts treated concomitantly with ultraviolet light. J Immunol. 1980 Jul;125(1):438–447. [PubMed] [Google Scholar]
- Sanger F., Coulson A. R., Barrell B. G., Smith A. J., Roe B. A. Cloning in single-stranded bacteriophage as an aid to rapid DNA sequencing. J Mol Biol. 1980 Oct 25;143(2):161–178. doi: 10.1016/0022-2836(80)90196-5. [DOI] [PubMed] [Google Scholar]
- Sher B. T., Nairn R., Coligan J. E., Hood L. E. DNA sequence of the mouse H-2Dd transplantation antigen gene. Proc Natl Acad Sci U S A. 1985 Feb;82(4):1175–1179. doi: 10.1073/pnas.82.4.1175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stroynowski I., Clark S., Henderson L. A., Hood L., McMillan M., Forman J. Interaction of alpha 1 with alpha 2 region in class I MHC proteins contributes determinants recognized by antibodies and cytotoxic T cells. J Immunol. 1985 Sep;135(3):2160–2166. [PubMed] [Google Scholar]
- Sun Y. H., Goodenow R. S., Hood L. Molecular basis of the dm1 mutation in the major histocompatibility complex of the mouse: a D/L hybrid gene. J Exp Med. 1985 Nov 1;162(5):1588–1602. doi: 10.1084/jem.162.5.1588. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Walker L. E., Ketler T. A., Houghten R. A., Schulz G., Chersi A., Reisfeld R. A. Human major histocompatibility complex class I antigens: residues 61-83 of the HLA-B7 heavy chain specify an alloreactive site. Proc Natl Acad Sci U S A. 1985 Jan;82(2):539–542. doi: 10.1073/pnas.82.2.539. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weiss E. H., Golden L., Fahrner K., Mellor A. L., Devlin J. J., Bullman H., Tiddens H., Bud H., Flavell R. A. Organization and evolution of the class I gene family in the major histocompatibility complex of the C57BL/10 mouse. Nature. 1984 Aug 23;310(5979):650–655. doi: 10.1038/310650a0. [DOI] [PubMed] [Google Scholar]
- Winoto A., Steinmetz M., Hood L. Genetic mapping in the major histocompatibility complex by restriction enzyme site polymorphisms: most mouse class I genes map to the Tla complex. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3425–3429. doi: 10.1073/pnas.80.11.3425. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wortzel R. D., Philipps C., Schreiber H. Multiple tumour-specific antigens expressed on a single tumour cell. Nature. 1983 Jul 14;304(5922):165–167. doi: 10.1038/304165a0. [DOI] [PubMed] [Google Scholar]
- Wortzel R. D., Urban J. L., Schreiber H. Malignant growth in the normal host after variant selection in vitro with cytolytic T-cell lines. Proc Natl Acad Sci U S A. 1984 Apr;81(7):2186–2190. doi: 10.1073/pnas.81.7.2186. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- 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]
