Abstract
To study the mechanisms of tolerance in detail, we have constructed transgenic mice expressing a V beta 8.1-D beta 2-J beta 2.3-C beta 2 T-cell receptor (TCR) gene. Since expression of V beta 8.1 is known to correlate with reactivity of CD4+CD8- T cells to minor lymphocyte-stimulating locus 1a (Mls-1a), we expected to induce tolerance in most CD4+CD8- T cells in V beta 8.1 transgenic mice of the Mls-1a allele. In one line of Mls-1b V beta 8.1 transgenic mice, the V beta 8.1 TCR was expressed on greater than 98% of mature T cells and their response to Mls-1a was highly enriched. In Mls-1a V beta 8.1 transgenic mice, CD4+CD8- T cells in these mice were severely reduced among both peripheral T cells and thymocytes. However, the deletion of these cells was not complete, and most of the residual CD4+CD8- mature T cells still expressed normal densities of V beta 8.1 TCR. The residual CD4+CD8- T cells did not respond to Mls-1a but were still able to proliferate in response to other stimuli via the TCR. Interestingly, CD4+CD8- V beta 8.1+ T-cell clones isolated from Mls-1a V beta 8.1 transgenic mice could respond to Mls-1a. We suggest that these types of T cells escape clonal deletion in the thymus.
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- Abe R., Ryan J. J., Finkelman F. D., Hodes R. J. T cell recognition of Mls. T cell clones demonstrate polymorphism between Mlsa, Mlsc, and Mlsd. J Immunol. 1987 Jan 15;138(2):373–379. [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]
- Berg L. J., Fazekas de St Groth B., Pullen A. M., Davis M. M. Phenotypic differences between alpha beta versus beta T-cell receptor transgenic mice undergoing negative selection. Nature. 1989 Aug 17;340(6234):559–562. doi: 10.1038/340559a0. [DOI] [PubMed] [Google Scholar]
- Berg L. J., Pullen A. M., Fazekas de St Groth B., Mathis D., Benoist C., Davis M. M. Antigen/MHC-specific T cells are preferentially exported from the thymus in the presence of their MHC ligand. Cell. 1989 Sep 22;58(6):1035–1046. doi: 10.1016/0092-8674(89)90502-3. [DOI] [PubMed] [Google Scholar]
- Burkly L. C., Lo D., Kanagawa O., Brinster R. L., Flavell R. A. T-cell tolerance by clonal anergy in transgenic mice with nonlymphoid expression of MHC class II I-E. Nature. 1989 Nov 30;342(6249):564–566. doi: 10.1038/342564a0. [DOI] [PubMed] [Google Scholar]
- DosReis G. A., Shevach E. M. Analysis of autoreactive I region-restricted T cell colonies isolated from the guinea pig syngeneic mixed leukocyte reaction and from immune responses to conventional foreign antigens. Eur J Immunol. 1985 May;15(5):466–472. doi: 10.1002/eji.1830150510. [DOI] [PubMed] [Google Scholar]
- Faherty D. A., Johnson D. R., Zauderer M. Origin and specificity of autoreactive T cells in antigen-induced populations. J Exp Med. 1985 Jun 1;161(6):1293–1301. doi: 10.1084/jem.161.6.1293. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Glasebrook A. L., Fitch F. W. Alloreactive cloned T cell lines. I. Interactions between cloned amplifier and cytolytic T cell lines. J Exp Med. 1980 Apr 1;151(4):876–895. doi: 10.1084/jem.151.4.876. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haskins K., Hannum C., White J., Roehm N., Kubo R., Kappler J., Marrack P. The antigen-specific, major histocompatibility complex-restricted receptor on T cells. VI. An antibody to a receptor allotype. J Exp Med. 1984 Aug 1;160(2):452–471. doi: 10.1084/jem.160.2.452. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Havran W. L., Poenie M., Kimura J., Tsien R., Weiss A., Allison J. P. Expression and function of the CD3-antigen receptor on murine CD4+8+ thymocytes. Nature. 1987 Nov 12;330(6144):170–173. doi: 10.1038/330170a0. [DOI] [PubMed] [Google Scholar]
- Kanagawa O., Palmer E., Bill J. The T cell receptor V beta 6 domain imparts reactivity to the Mls-1a antigen. Cell Immunol. 1989 Apr 1;119(2):412–426. doi: 10.1016/0008-8749(89)90255-4. [DOI] [PubMed] [Google Scholar]
- Kappler J. W., Roehm N., Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987 Apr 24;49(2):273–280. doi: 10.1016/0092-8674(87)90568-x. [DOI] [PubMed] [Google Scholar]
- Kappler J. W., Staerz U., White J., Marrack P. C. Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex. Nature. 1988 Mar 3;332(6159):35–40. doi: 10.1038/332035a0. [DOI] [PubMed] [Google Scholar]
- Kaye J., Hsu M. L., Sauron M. E., Jameson S. C., Gascoigne N. R., Hedrick S. M. Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor. Nature. 1989 Oct 26;341(6244):746–749. doi: 10.1038/341746a0. [DOI] [PubMed] [Google Scholar]
- Kisielow P., Blüthmann H., Staerz U. D., Steinmetz M., von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988 Jun 23;333(6175):742–746. doi: 10.1038/333742a0. [DOI] [PubMed] [Google Scholar]
- Krimpenfort P., de Jong R., Uematsu Y., Dembic Z., Ryser S., von Boehmer H., Steinmetz M., Berns A. Transcription of T cell receptor beta-chain genes is controlled by a downstream regulatory element. EMBO J. 1988 Mar;7(3):745–750. doi: 10.1002/j.1460-2075.1988.tb02871.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kubo R. T., Born W., Kappler J. W., Marrack P., Pigeon M. Characterization of a monoclonal antibody which detects all murine alpha beta T cell receptors. J Immunol. 1989 Apr 15;142(8):2736–2742. [PubMed] [Google Scholar]
- Lo D., Burkly L. C., Widera G., Cowing C., Flavell R. A., Palmiter R. D., Brinster R. L. Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic beta cells. Cell. 1988 Apr 8;53(1):159–168. doi: 10.1016/0092-8674(88)90497-7. [DOI] [PubMed] [Google Scholar]
- MacDonald H. R., Schneider R., Lees R. K., Howe R. C., Acha-Orbea H., Festenstein H., Zinkernagel R. M., Hengartner H. T-cell receptor V beta use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature. 1988 Mar 3;332(6159):40–45. doi: 10.1038/332040a0. [DOI] [PubMed] [Google Scholar]
- Ozato K., Mayer N. M., Sachs D. H. Monoclonal antibodies to mouse major histocompatibility complex antigens. Transplantation. 1982 Sep;34(3):113–120. doi: 10.1097/00007890-198209000-00001. [DOI] [PubMed] [Google Scholar]
- Pircher H., Bürki K., Lang R., Hengartner H., Zinkernagel R. M. Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature. 1989 Nov 30;342(6249):559–561. doi: 10.1038/342559a0. [DOI] [PubMed] [Google Scholar]
- Pircher H., Mak T. W., Lang R., Ballhausen W., Rüedi E., Hengartner H., Zinkernagel R. M., Bürki K. T cell tolerance to Mlsa encoded antigens in T cell receptor V beta 8.1 chain transgenic mice. EMBO J. 1989 Mar;8(3):719–727. doi: 10.1002/j.1460-2075.1989.tb03431.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Qin S. X., Cobbold S., Benjamin R., Waldmann H. Induction of classical transplantation tolerance in the adult. J Exp Med. 1989 Mar 1;169(3):779–794. doi: 10.1084/jem.169.3.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rammensee H. G., Kroschewski R., Frangoulis B. Clonal anergy induced in mature V beta 6+ T lymphocytes on immunizing Mls-1b mice with Mls-1a expressing cells. Nature. 1989 Jun 15;339(6225):541–544. doi: 10.1038/339541a0. [DOI] [PubMed] [Google Scholar]
- Ramsdell F., Lantz T., Fowlkes B. J. A nondeletional mechanism of thymic self tolerance. Science. 1989 Nov 24;246(4933):1038–1041. doi: 10.1126/science.2511629. [DOI] [PubMed] [Google Scholar]
- Sha W. C., Nelson C. A., Newberry R. D., Kranz D. M., Russell J. H., Loh D. Y. Positive and negative selection of an antigen receptor on T cells in transgenic mice. Nature. 1988 Nov 3;336(6194):73–76. doi: 10.1038/336073a0. [DOI] [PubMed] [Google Scholar]
- Staerz U. D., Rammensee H. G., Benedetto J. D., Bevan M. J. Characterization of a murine monoclonal antibody specific for an allotypic determinant on T cell antigen receptor. J Immunol. 1985 Jun;134(6):3994–4000. [PubMed] [Google Scholar]
- Teh H. S., Kishi H., Scott B., Von Boehmer H. Deletion of autospecific T cells in T cell receptor (TCR) transgenic mice spares cells with normal TCR levels and low levels of CD8 molecules. J Exp Med. 1989 Mar 1;169(3):795–806. doi: 10.1084/jem.169.3.795. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Teh H. S., Kisielow P., Scott B., Kishi H., Uematsu Y., Blüthmann H., von Boehmer H. Thymic major histocompatibility complex antigens and the alpha beta T-cell receptor determine the CD4/CD8 phenotype of T cells. Nature. 1988 Sep 15;335(6187):229–233. doi: 10.1038/335229a0. [DOI] [PubMed] [Google Scholar]
- Tilkin A. F., Michon J., Juy D., Kayibanda M., Henin Y., Sterkers G., Betuel H., Lévy J. P. Autoreactive T cell clones of MHC class II specificities are produced during responses against foreign antigens in man. J Immunol. 1987 Feb 1;138(3):674–679. [PubMed] [Google Scholar]
- Uematsu Y., Ryser S., Dembić Z., Borgulya P., Krimpenfort P., Berns A., von Boehmer H., Steinmetz M. In transgenic mice the introduced functional T cell receptor beta gene prevents expression of endogenous beta genes. Cell. 1988 Mar 25;52(6):831–841. doi: 10.1016/0092-8674(88)90425-4. [DOI] [PubMed] [Google Scholar]
- Wadsworth S., Yui K., Siegel R. M., Tenenholz D. E., Hirsch J. A., Greene M. I. Origin and selection of peripheral CD4-CD8- T cells bearing alpha/beta T cell antigen receptors in autoimmune gld mice. Eur J Immunol. 1990 Apr;20(4):723–730. doi: 10.1002/eji.1830200403. [DOI] [PubMed] [Google Scholar]
- White J., Herman A., Pullen A. M., Kubo R., Kappler J. W., Marrack P. The V beta-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice. Cell. 1989 Jan 13;56(1):27–35. doi: 10.1016/0092-8674(89)90980-x. [DOI] [PubMed] [Google Scholar]
- Yui K., Hashimoto Y., Wadsworth S., Greene M. I. Characterization of Lyt-2-, L3T4- class I-specific cytolytic clones in C3H-gld/gld mice. Implications for functions of accessory molecules and programmed development. J Exp Med. 1987 Oct 1;166(4):1026–1040. doi: 10.1084/jem.166.4.1026. [DOI] [PMC free article] [PubMed] [Google Scholar]