Abstract
Mouse mammary tumor virus (MMTV)-encoded superantigens (SAGs) influence the murine T cell repertoire and stimulate a strong mixed lymphocyte response in vitro. These SAGs are encoded by the open reading frame of the 3' long terminal repeat of MMTV, termed MMTV SAGs. The T cell response to MMTV SAGs is V beta restricted and requires expression of the class II molecules of the major histocompatibility complex (MHC) on the presenting cells. While human T cells respond to bacterial SAGs, it is not known if human T cells or human MHC class II molecules can interact with MMTV SAGs. A fibroblastic cell line expressing the human MHC class II molecule HLA-DR1 and the Mtv-7 sag gene encoding Mls-1 was used to stimulate human T cells. We show here that human T cells efficiently proliferate in response to Mls-1 presented by HLA-DR1. This T cell response was inhibited by mAbs directed against CD4 or MHC class II molecules but not by mAbs specific for CD8 or MHC class I molecules. Moreover, the response to Mls-1 was limited to human T cells expressing a restricted set of T cell receptor V beta chains. Human T cells expressing V beta 12, 13, 14, 15, and 23 were selectively amplified after Mtv-7 sag stimulation. Interestingly, these human V beta s share the highest degree of homology with the mouse V beta s interacting with Mls-1. These results show a strong evolutionary conservation of the structures required for the presentation and the response to retrovirally encoded endogenous SAGs, raising the possibility that similar elements operate in humans to shape the T cell repertoire.
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.
- Acha-Orbea H., Palmer E. Mls--a retrovirus exploits the immune system. Immunol Today. 1991 Oct;12(10):356–361. doi: 10.1016/0167-5699(91)90066-3. [DOI] [PubMed] [Google Scholar]
- Acha-Orbea H., Shakhov A. N., Scarpellino L., Kolb E., Müller V., Vessaz-Shaw A., Fuchs R., Blöchlinger K., Rollini P., Billotte J. Clonal deletion of V beta 14-bearing T cells in mice transgenic for mammary tumour virus. Nature. 1991 Mar 21;350(6315):207–211. doi: 10.1038/350207a0. [DOI] [PubMed] [Google Scholar]
- Beutner U., Frankel W. N., Cote M. S., Coffin J. M., Huber B. T. Mls-1 is encoded by the long terminal repeat open reading frame of the mouse mammary tumor provirus Mtv-7. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5432–5436. doi: 10.1073/pnas.89.12.5432. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Carrel S., Isler P., Schreyer M., Vacca A., Salvi S., Giuffre L., Mach J. P. Expression on human thymocytes of the idiotypic structures (Ti) from two leukemia T cell lines Jurkat and HPB-ALL. Eur J Immunol. 1986 Jun;16(6):649–652. doi: 10.1002/eji.1830160610. [DOI] [PubMed] [Google Scholar]
- Cazenave P. A., Marche P. N., Jouvin-Marche E., Voegtlé D., Bonhomme F., Bandeira A., Coutinho A. V beta 17 gene polymorphism in wild-derived mouse strains: two amino acid substitutions in the V beta 17 region greatly alter T cell receptor specificity. Cell. 1990 Nov 16;63(4):717–728. doi: 10.1016/0092-8674(90)90138-5. [DOI] [PubMed] [Google Scholar]
- Choi Y., Kappler J. W., Marrack P. A superantigen encoded in the open reading frame of the 3' long terminal repeat of mouse mammary tumour virus. Nature. 1991 Mar 21;350(6315):203–207. doi: 10.1038/350203a0. [DOI] [PubMed] [Google Scholar]
- DeKruyff R. H., Ju S. T., Laning J., Cantor H., Dorf M. E. Activation requirements of cloned inducer T cells. III. Need for two stimulator cells in the response of a cloned line to Mls determinants. J Immunol. 1986 Aug 15;137(4):1109–1114. [PubMed] [Google Scholar]
- Dyson P. J., Knight A. M., Fairchild S., Simpson E., Tomonari K. Genes encoding ligands for deletion of V beta 11 T cells cosegregate with mammary tumour virus genomes. Nature. 1991 Feb 7;349(6309):531–532. doi: 10.1038/349531a0. [DOI] [PubMed] [Google Scholar]
- Ferradini L., Roman-Roman S., Azocar J., Michalaki H., Triebel F., Hercend T. Studies on the human T cell receptor alpha/beta variable region genes. II. Identification of four additional V beta subfamilies. Eur J Immunol. 1991 Apr;21(4):935–942. doi: 10.1002/eji.1830210412. [DOI] [PubMed] [Google Scholar]
- Festenstein H. Immunogenetic and biological aspects of in vitro lymphocyte allotransformation (MLR) in the mouse. Transplant Rev. 1973;15:62–88. doi: 10.1111/j.1600-065x.1973.tb00111.x. [DOI] [PubMed] [Google Scholar]
- Frankel W. N., Rudy C., Coffin J. M., Huber B. T. Linkage of Mls genes to endogenous mammary tumour viruses of inbred mice. Nature. 1991 Feb 7;349(6309):526–528. doi: 10.1038/349526a0. [DOI] [PubMed] [Google Scholar]
- Friedman S. M., Crow M. K., Tumang J. R., Tumang M., Xu Y. Q., Hodtsev A. S., Cole B. C., Posnett D. N. Characterization of human T cells reactive with the Mycoplasma arthritidis-derived superantigen (MAM): generation of a monoclonal antibody against V beta 17, the T cell receptor gene product expressed by a large fraction of MAM-reactive human T cells. J Exp Med. 1991 Oct 1;174(4):891–900. doi: 10.1084/jem.174.4.891. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Golovkina T. V., Chervonsky A., Dudley J. P., Ross S. R. Transgenic mouse mammary tumor virus superantigen expression prevents viral infection. Cell. 1992 May 15;69(4):637–645. doi: 10.1016/0092-8674(92)90227-4. [DOI] [PubMed] [Google Scholar]
- Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
- Gunning P., Leavitt J., Muscat G., Ng S. Y., Kedes L. A human beta-actin expression vector system directs high-level accumulation of antisense transcripts. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4831–4835. doi: 10.1073/pnas.84.14.4831. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Happ M. P., Woodland D. L., Palmer E. A third T-cell receptor beta-chain variable region gene encodes reactivity to Mls-1a gene products. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6293–6296. doi: 10.1073/pnas.86.16.6293. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Held W., Shakhov A. N., Waanders G., Scarpellino L., Luethy R., Kraehenbuhl J. P., MacDonald H. R., Acha-Orbea H. An exogenous mouse mammary tumor virus with properties of Mls-1a (Mtv-7). J Exp Med. 1992 Jun 1;175(6):1623–1633. doi: 10.1084/jem.175.6.1623. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Herman A., Kappler J. W., Marrack P., Pullen A. M. Superantigens: mechanism of T-cell stimulation and role in immune responses. Annu Rev Immunol. 1991;9:745–772. doi: 10.1146/annurev.iy.09.040191.003525. [DOI] [PubMed] [Google Scholar]
- Howell M. D., Diveley J. P., Lundeen K. A., Esty A., Winters S. T., Carlo D. J., Brostoff S. W. Limited T-cell receptor beta-chain heterogeneity among interleukin 2 receptor-positive synovial T cells suggests a role for superantigen in rheumatoid arthritis. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10921–10925. doi: 10.1073/pnas.88.23.10921. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hügin A. W., Vacchio M. S., Morse H. C., 3rd A virus-encoded "superantigen" in a retrovirus-induced immunodeficiency syndrome of mice. Science. 1991 Apr 19;252(5004):424–427. doi: 10.1126/science.1850169. [DOI] [PubMed] [Google Scholar]
- Imberti L., Sottini A., Bettinardi A., Puoti M., Primi D. Selective depletion in HIV infection of T cells that bear specific T cell receptor V beta sequences. Science. 1991 Nov 8;254(5033):860–862. doi: 10.1126/science.1948066. [DOI] [PubMed] [Google Scholar]
- Kanagawa O., Nussrallah B. A., Wiebenga M. E., Murphy K. M., Morse H. C., 3rd, Carbone F. R. Murine AIDS superantigen reactivity of the T cells bearing V beta 5 T cell antigen receptor. J Immunol. 1992 Jul 1;149(1):9–16. [PubMed] [Google Scholar]
- Kappler J., Kotzin B., Herron L., Gelfand E. W., Bigler R. D., Boylston A., Carrel S., Posnett D. N., Choi Y., Marrack P. V beta-specific stimulation of human T cells by staphylococcal toxins. Science. 1989 May 19;244(4906):811–813. doi: 10.1126/science.2524876. [DOI] [PubMed] [Google Scholar]
- Katz M. E., Janeway C. A., Jr The immunobiology of T cell responses to Mls-locus-disparate stimulator cells. II. Effects of Mls-locus-disparate stimulator cells on cloned, protein antigen-specific, Ia-restricted T cell lines. J Immunol. 1985 Apr;134(4):2064–2070. [PubMed] [Google Scholar]
- Lafon M., Lafage M., Martinez-Arends A., Ramirez R., Vuillier F., Charron D., Lotteau V., Scott-Algara D. Evidence for a viral superantigen in humans. Nature. 1992 Aug 6;358(6386):507–510. doi: 10.1038/358507a0. [DOI] [PubMed] [Google Scholar]
- Laurence J., Hodtsev A. S., Posnett D. N. Superantigen implicated in dependence of HIV-1 replication in T cells on TCR V beta expression. Nature. 1992 Jul 16;358(6383):255–259. doi: 10.1038/358255a0. [DOI] [PubMed] [Google Scholar]
- Lechler R. I., Norcross M. A., Germain R. N. Qualitative and quantitative studies of antigen-presenting cell function by using I-A-expressing L cells. J Immunol. 1985 Nov;135(5):2914–2922. [PubMed] [Google Scholar]
- Li Y., Szabo P., Robinson M. A., Dong B., Posnett D. N. Allelic variations in the human T cell receptor V beta 6.7 gene products. J Exp Med. 1990 Jan 1;171(1):221–230. doi: 10.1084/jem.171.1.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- MacDonald H. R., Lees R. K., Chvatchko Y. CD8+ T cells respond clonally to Mls-1a-encoded determinants. J Exp Med. 1990 Apr 1;171(4):1381–1386. doi: 10.1084/jem.171.4.1381. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marrack P., Kappler J. The staphylococcal enterotoxins and their relatives. Science. 1990 May 11;248(4956):705–711. doi: 10.1126/science.2185544. [DOI] [PubMed] [Google Scholar]
- Marrack P., Kushnir E., Kappler J. A maternally inherited superantigen encoded by a mammary tumour virus. Nature. 1991 Feb 7;349(6309):524–526. doi: 10.1038/349524a0. [DOI] [PubMed] [Google Scholar]
- Paliard X., West S. G., Lafferty J. A., Clements J. R., Kappler J. W., Marrack P., Kotzin B. L. Evidence for the effects of a superantigen in rheumatoid arthritis. Science. 1991 Jul 19;253(5017):325–329. doi: 10.1126/science.1857971. [DOI] [PubMed] [Google Scholar]
- Papiernik M., Pontoux C., Gisselbrecht S. Acquired Mls-1a-like clonal deletion in Mls-1b mice. J Exp Med. 1992 Feb 1;175(2):453–460. doi: 10.1084/jem.175.2.453. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Posnett D. N., Wang C. Y., Friedman S. M. Inherited polymorphism of the human T-cell antigen receptor detected by a monoclonal antibody. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7888–7892. doi: 10.1073/pnas.83.20.7888. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pullen A. M., Bill J., Kubo R. T., Marrack P., Kappler J. W. Analysis of the interaction site for the self superantigen Mls-1a on T cell receptor V beta. J Exp Med. 1991 May 1;173(5):1183–1192. doi: 10.1084/jem.173.5.1183. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pullen A. M., Wade T., Marrack P., Kappler J. W. Identification of the region of T cell receptor beta chain that interacts with the self-superantigen MIs-1a. Cell. 1990 Jun 29;61(7):1365–1374. doi: 10.1016/0092-8674(90)90700-o. [DOI] [PubMed] [Google Scholar]
- Robinson M. A. Allelic sequence variations in the hypervariable region of a T-cell receptor beta chain: correlation with restriction fragment length polymorphism in human families and populations. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9422–9426. doi: 10.1073/pnas.86.23.9422. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Seboun E., Robinson M. A., Doolittle T. H., Ciulla T. A., Kindt T. J., Hauser S. L. A susceptibility locus for multiple sclerosis is linked to the T cell receptor beta chain complex. Cell. 1989 Jun 30;57(7):1095–1100. doi: 10.1016/0092-8674(89)90046-9. [DOI] [PubMed] [Google Scholar]
- Seboun E., Robinson M. A., Kindt T. J., Hauser S. L. Insertion/deletion-related polymorphisms in the human T cell receptor beta gene complex. J Exp Med. 1989 Oct 1;170(4):1263–1270. doi: 10.1084/jem.170.4.1263. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sottini A., Imberti L., Gorla R., Cattaneo R., Primi D. Restricted expression of T cell receptor V beta but not V alpha genes in rheumatoid arthritis. Eur J Immunol. 1991 Feb;21(2):461–466. doi: 10.1002/eji.1830210231. [DOI] [PubMed] [Google Scholar]
- Uematsu Y., Wege H., Straus A., Ott M., Bannwarth W., Lanchbury J., Panayi G., Steinmetz M. The T-cell-receptor repertoire in the synovial fluid of a patient with rheumatoid arthritis is polyclonal. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8534–8538. doi: 10.1073/pnas.88.19.8534. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Webb S. R., Sprent J. Response of mature unprimed CD8+ T cells to Mlsa determinants. J Exp Med. 1990 Mar 1;171(3):953–958. doi: 10.1084/jem.171.3.953. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wilson R. K., Lai E., Concannon P., Barth R. K., Hood L. E. Structure, organization and polymorphism of murine and human T-cell receptor alpha and beta chain gene families. Immunol Rev. 1988 Jan;101:149–172. doi: 10.1111/j.1600-065x.1988.tb00736.x. [DOI] [PubMed] [Google Scholar]
- Woodland D. L., Happ M. P., Gollob K. J., Palmer E. An endogenous retrovirus mediating deletion of alpha beta T cells? Nature. 1991 Feb 7;349(6309):529–530. doi: 10.1038/349529a0. [DOI] [PubMed] [Google Scholar]
- Woodland D. L., Lund F. E., Happ M. P., Blackman M. A., Palmer E., Corley R. B. Endogenous superantigen expression is controlled by mouse mammary tumor proviral loci. J Exp Med. 1991 Nov 1;174(5):1255–1258. doi: 10.1084/jem.174.5.1255. [DOI] [PMC free article] [PubMed] [Google Scholar]