Abstract
The ability to mount an immune response to simian virus 40 (SV40) T antigen was evaluated using mice from two distinct SV40 transgenic lines derived from injection of the same gene construct. Our studies demonstrate functional immune tolerance to SV40 T antigen in a SV40 transgenic line that consistently develops tumors of the choroid plexus by 7 mo of age. Antibodies to SV40 T antigen are undetectable in the serum of these animals; furthermore, mice from this line are unable to generate SV40-specific CTL after primary or secondary immunization with the virus, although they mount a normal CTL response to vaccinia virus when appropriately immunized. In contrast, we find that mice from a second transgenic line of low tumor incidence can mount a humoral response to SV40 T antigen, and upon immunization they generally respond with a vigorous cytotoxic T cell response to SV40 T antigen. These data suggest that specific immune tolerance to the product of an integrated viral oncogene may be induced, and is likely a reflection of the time in development at which the gene product first appears. Immune tolerance or responsiveness to the endogenous oncogene product may in turn play a role in the tumorigenic potential of such genes.
Full Text
The Full Text of this article is available as a PDF (651.5 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Abramczuk J., Pan S., Maul G., Knowles B. B. Tumor induction by simian virus 40 in mice is controlled by long-term persistence of the viral genome and the immune response of the host. J Virol. 1984 Feb;49(2):540–548. doi: 10.1128/jvi.49.2.540-548.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- BILLINGHAM R. E., BRENT L., MEDAWAR P. B. Actively acquired tolerance of foreign cells. Nature. 1953 Oct 3;172(4379):603–606. doi: 10.1038/172603a0. [DOI] [PubMed] [Google Scholar]
- Banerji J., Olson L., Schaffner W. A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes. Cell. 1983 Jul;33(3):729–740. doi: 10.1016/0092-8674(83)90015-6. [DOI] [PubMed] [Google Scholar]
- Chisari F. V., Pinkert C. A., Milich D. R., Filippi P., McLachlan A., Palmiter R. D., Brinster R. L. A transgenic mouse model of the chronic hepatitis B surface antigen carrier state. Science. 1985 Dec 6;230(4730):1157–1160. doi: 10.1126/science.3865369. [DOI] [PubMed] [Google Scholar]
- Dorsch S., Roser R. Recirculating, suppressor T cells in transplantation tolerance. J Exp Med. 1977 May 1;145(5):1144–1157. doi: 10.1084/jem.145.5.1144. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gillies S. D., Folsom V., Tonegawa S. Cell type-specific enhancer element associated with a mouse MHC gene, E beta. Nature. 1984 Aug 16;310(5978):594–597. doi: 10.1038/310594a0. [DOI] [PubMed] [Google Scholar]
- Gillies S. D., Morrison S. L., Oi V. T., Tonegawa S. A tissue-specific transcription enhancer element is located in the major intron of a rearranged immunoglobulin heavy chain gene. Cell. 1983 Jul;33(3):717–728. doi: 10.1016/0092-8674(83)90014-4. [DOI] [PubMed] [Google Scholar]
- 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]
- Gooding L. R. Specificities of killing by cytotoxic lymphocytes generated in vivo and in vitro to syngeneic SV40 transformed cells. J Immunol. 1977 Mar;118(3):920–927. [PubMed] [Google Scholar]
- Gruchalla R. S., Streilein J. W. Analysis of neonatally induced tolerance of H-2 alloantigens. II. Failure to detect alloantigen-specific T-lymphocyte precursors and suppressors. Immunogenetics. 1982;15(2):111–127. doi: 10.1007/BF00621945. [DOI] [PubMed] [Google Scholar]
- Hanahan D. Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature. 1985 May 9;315(6015):115–122. doi: 10.1038/315115a0. [DOI] [PubMed] [Google Scholar]
- Knowles B. B., Ford S. R., Aden D. P. Reactivity to SV40 T antigen in athymic (nude), anti-thymocyte serum-treated, and normal mice. J Immunol. 1977 Jul;119(1):79–82. [PubMed] [Google Scholar]
- Knowles B. B., Koncar M., Pfizenmaier K., Solter D., Aden D. P., Trinchieri G. Genetic control of the cytotoxic T cell response to SV40 tumor-associated specific antigen. J Immunol. 1979 May;122(5):1798–1806. [PubMed] [Google Scholar]
- Korngold R., Bennink J. R., Doherty P. C. Early dominance of irradiated host cells in the responder profiles of thymocytes from P leads to F1 radiation chimeras. J Immunol. 1981 Jul;127(1):124–129. [PubMed] [Google Scholar]
- Nossal G. J., Pike B. L. Functional clonal deletion in immunological tolerance to major histocompatibility complex antigens. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3844–3847. doi: 10.1073/pnas.78.6.3844. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Palmiter R. D., Chen H. Y., Messing A., Brinster R. L. SV40 enhancer and large-T antigen are instrumental in development of choroid plexus tumours in transgenic mice. Nature. 1985 Aug 1;316(6027):457–460. doi: 10.1038/316457a0. [DOI] [PubMed] [Google Scholar]
- Pan S., Knowles B. B. Monoclonal antibody to SV40 T-antigen blocks lysis of cloned cytotoxic T-cell line specific for SV40 TASA. Virology. 1983 Feb;125(1):1–7. doi: 10.1016/0042-6822(83)90058-2. [DOI] [PubMed] [Google Scholar]
- Stockinger B. Cytotoxic T-cell precursors revealed in neonatally tolerant mice. Proc Natl Acad Sci U S A. 1984 Jan;81(1):220–223. doi: 10.1073/pnas.81.1.220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tevethia S. S., Blasecki J. W., Waneck G., Goldstein A. L. Requirement of thymus-derived theta-positive lymphocytes for rejection of DNA virus (SV 40) tumors in mice. J Immunol. 1974 Nov;113(5):1417–1423. [PubMed] [Google Scholar]
- Van Dyke T., Finlay C., Levine A. J. A comparison of several lines of transgenic mice containing the SV40 early genes. Cold Spring Harb Symp Quant Biol. 1985;50:671–678. doi: 10.1101/sqb.1985.050.01.082. [DOI] [PubMed] [Google Scholar]
- Weigle W. O. Immunological unresponsiveness. Adv Immunol. 1973;16:61–122. doi: 10.1016/s0065-2776(08)60296-5. [DOI] [PubMed] [Google Scholar]
- Wood P. J., Streilein J. W. Ontogeny of acquired immunological tolerance to H-2 alloantigens. Eur J Immunol. 1982 Mar;12(3):188–194. doi: 10.1002/eji.1830120304. [DOI] [PubMed] [Google Scholar]
