Abstract
We have established a strain of transgenic mice in which the HLA-DRA gene was integrated into the X-chromosome and the xenogeneic mixed isotype molecule, DRαEβb, was expressed in a cell type-specific manner, although the transgenic DRA gene contained only 268 base pairs of the 5′-flanking region. The DRαEβb molecules expressed in the transgenic mice functioned as major histocompatibility complex (MHC) class II to select T-cell repertoire, and to stimulate mixed lymphocyte reaction. In female transgenic mice homozygous for HLA-DRA (DRα-B6-F-homo) and male transgenic mice (DRα-B6-M), DRαEβb molecules were expressed in almost all of the MHC class II Ab-positive cells. In contrast, the expression of DRαEβb molecules in female transgenic mice hemizygous for HLA-DRA (DRα-B6-F-hemi) was found only in part of the Ab positive cells, and the proportion of cells expressing the DRαEβb molecules varied due to random inactivation of one of the X-chromosomes. Clonal deletions of the T cells and mature thymocytes bearing Tcrb-V5 and Tcrb-V11, which are eliminated from the peripheral repertoire in mice expressing self-superantigen and MHC class II E molecules, were incomplete in DRα-B6-F-hemi as compared with those in DRα-B6-F-homo, and were correlated with the proportion of DRαEβb-positive spleen cells. These observations suggested that the number of bone marrow-derived cells expressing DRαEβb molecules was critical for clonal deletions of Tcrb-V5+ and Tcrb-V11+ T cells in the thymus.
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Abe, R., Kanagawa, O., Sheard, M. A., Malissen, B., and Foo-Philips, M.: Characterization of a new minor lymphocyte stimulatory system. I. Cluster of self antigens recognized by “I-E-reactive” Vβs, Vβ5, Vβ11, and Vβ12 T-cell receptors for antigen. J Immunol 147: 739–749, 1991
Altmann, D. M., Sansom, D., and Marsh, S. G. E.: What is the basis for HLA-DQ associations with autoimmune disease? Immunol Today 12: 267–270, 1991
Bill, J., Kanagawa, O., Woodland, D. L., and Palmer, E.: The MHC molecules I-E is necessary but not sufficient for the clonal deletion of Vβ11-bearing T cells. J Exp Med 169: 1405–1419, 1989
Blackman, M., Kappler, J., and Marrack, P.: The role of the T-cell repertoire in positive and negative selection of developing T cells. Science 248: 1335–1341, 1990
Bruce, J., Symington, F. W., Mckearn, T. J., and Sprent, J.: A monoclonal antibody discriminating between subsets of T and B cell. J Immunol 127: 2496–2501, 1981
Burkly, L. C., Lo, D., Cowing, C., Palmiter, R. D., Brinster, R. L., and Flavell, R. A.: Selective expression of class II Eαd gene in transgenic mice: J Immunol 142: 2081–2088, 1989
Crowley, M., Inaba, K., Witmer-Pack, M., and Steinman, R. M.: The cell surface of mouse dendritic cells: FACS analysis of dendritic cells from different tissues including thymus. Cell Immunol 118: 108–125, 1989
Dorn, A., Fehling, H. J., Koch, W., le Meur, M., Gerlinger, P., Benoist, C., and Matis, D.: B-cell control region at the 5′ end of a major histocompatibility complex class II gene: Sequence and Factors. Mol Cell Biol 8: 3975–3987, 1988
Fujisawa, K., Kamikawaji, N., Yasunami, M., Kimura, A., Nishimura, Y., and Sasazuki, T.: High precursor frequency of human T cells reactive to HLA-DQ molecules expressed on mouse L cell transfectants. Eur J Immunol 21: 2341–2347, 1991
Giacomini, P., Ciucci, A., Nicotra, M. R., Nastruzzi, C., Feriotto, G., Appella, E., Gambari, R., Pozzi, L., and Natali, P. G.: Tissue-specific expression of the HLA-DRA gene in transgenic mice. Immunogenetics 34: 385–391, 1991
Hirayama, K., Matsushita, S., Kikuchi, I., Iuchi, M., Ohta, N., and Sasazuki, T.: HLA-DQ is epistatic to HLA-DR in controlling immune response to schistosomal antigen in humans. Nature 327: 426–430, 1987
Inamitsu, T., Nishimura, Y., and Sasazuki, T.: Different recognition of transgenic HLA-DQw6 molecules by mouse CD4+ and CD8+ T cells. Immunogenetics 35: 46–50, 1992
Kamikawaji, N., Fujisawa, K., Yoshizumi, H., Fukunaga, M., Yasunami, M., Kimura, A., Nishimura, Y., and Sasazuki, T.: HLA-DQ-restricted CD4+ T cells specific to streptococcal antigen present in low but not high responders. J Immunol 146: 2560–2567, 1991
Kisielow, P., Blüthmann, H., Staerz, U. D., Steinmetz, M., and von Boehmer, H.: Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+ CD8+ thymocytes. Nature 333: 742–746, 1988
Lawrance, S. K., Karlsson, L., Price, J., Quaranta, V., Ron, Y., Sprent, J., and Peterson, P. A.: Transgenic HLA-DRα faithfully reconstitutes IE-controlled immune functions and induces cross-tolerance to Eα in Eαo mutant mice. Cell 58: 583–594, 1989
Lerner, E. A., Matis, L. A., Janeway, C. A. Jr., Jones, P. P., Schwartz, R. H., and Murphy, D. B.: Monoclonal antibody against an Ir gene product? J Exp Med 152: 1085–1101, 1980
Lyon, M. F.: The William Allan Memorial Award address: X-chromosome inactivation and the location and expression of X-linked genes. Am J Hum Genet 42: 8–16, 1988
Marrack, P., Lo, D., Brinster, R., Palmiter, R., Burkly, L., Flavell, R. H., and Kappler, J.: The effect of thymus environment on T cell development and tolerance. Cell 53: 627–634, 1988
Mazda, O., Watanabe, Y., Gyotoku, J.-I., and Katsura, Y.: Requirement of dendritic cells and B cells in the clonal deletion of Mls-reactive T cells in the thymus. J Exp Med 173: 539–547, 1991
Nussenzweig, M. C., Steinman, R. M., Witmer, M. D., and Gutchinov, B.: A monoclonal antibody specific for mouse dendritic cells. Proc Natl Acad Sci USA 79: 161–165, 1982
Okada, C. Y. and Weissman, I. L.: Relative Vβ transcript levels in thymus and peripheral lymphoid tissues from various mouse strains. J Exp Med 169: 1703–1719, 1989
Ozato, K., Mayer, N., and Sachs, D. H.: Hybridoma cell lines secreting monoclonal antibodies to mouse H-2 and Ia antigens. J Immunol 124: 533–540, 1980
Rastan, S.: Timing of X-chromosome inactivation in postimplantation embryos. J Embryol Exp Morph 71: 11–24, 1982
Sha, W. C., Nelson, C. A., Newberry, R. D., Kranz, D. M., Russell, J. H., and Loh, D. Y.: Positive and negative selection of an antigen receptor on T cells in transgenic mice. Nature 336: 73–76, 1988
Sherman, P. A., Basta, P. V., and Ting, J. P.-Y.: Upstream DNA sequences required for tissue-specific expression of the HLA-DRα gene complex. Proc Natl Acad Sci USA 84: 4254–4258, 1987
Tomonari, K. and Lovering, E.: T-cell receptor-specific monoclonal antibodies against a Vβ11-positive mouse T-cell clone. Immunogenetics 28: 445–451, 1988
Tsang, S. Y., Nakinishi, M., and Peterlin, B. M.: B-cell-specific and interferon-γ-inducible regulation of the HLA-DRα gene. Proc Natl Acad Sci USA 85: 8598–8602, 1988
van Ewijk, W., Ron, Y., Monaco, J., Kappler, J., Marrack, P., Meur, M. L., Gerlinger, P., Durand, B., Benoist,C., and Matis, D.: Compartmentalization of MHC class II gene expression in transgenic mice. Cell 53: 357–370, 1988
Widera, G., Burkly, L. C., Pinkert, C. A., Böttger, E. C., Cowing, C., Palmiter, R. D., Brinster, R. L., and Flavell, R. A.: Transgenic mice selectively lacking MHC class II (I-E) antigen expression on B cells: An in vivo approach to investigate Ia gene function. Cell 51: 175–187, 1987
Woodland, D., Happ, M. P., Bill, J., and Palmer, E.: Requirement for cotolerogenic gene products in the clonal deletion of I-E reactive T cells. Science 247: 964–967, 1990
Yamamura, K., Kikutani, H., Folsom, V., Clayton, L. C., Kimoto, M., Akira, S., Kashiwamura, S., Tonegawa, S., and Kishimoto, T.: Functional expression of a microinjected Eαd gene in C57BL/6 transgenic mice. Nature 316: 67–69, 1985
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Fukui, Y., Esaki, Y., Kimura, A. et al. T-cell repertoire in a strain of transgenic C57BL/6 mice with the HLA-DRA gene on the X-chromosome. Immunogenetics 37, 204–211 (1993). https://doi.org/10.1007/BF00191886
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DOI: https://doi.org/10.1007/BF00191886