Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

HLA-linkedImmune suppression genes

Japanese journal of human genetics volume 35, pages 1–13 (1990)Cite this article

Summary

Genetic control of immune response was investigated by family and population analyses in humans. It was first recognized that there are high responders and low or non responders to natural antigens in human population. Family analysis revealed that low responsiveness to streptococcal cell wall antigen (SCW) was inherited as anHLA-linked dominant trait. CD8+ suppressor T cells existed in low responders and depletion of the CD8+ T cells from low responders could restore the strong immune response to SCW. Therefore the gene controlling the low response to SCW was designated as animmune suppression gene for SCW.Immune suppression gene for SCW was in strong linkage disequilibrium with particular alleles ofHLA-DQ locus. The association betweenHLA-DQ alleles and low responsiveness mediated by CD8+ suppressor T cell was also observed for schistosomal antigen,Mycobacterium leprae antigen, tetanus toxoid, cryptomeria pollen antigen and hepatitis B virus surface antigen suggesting that low responsiveness to those antigens was also controlled byimmune suppression genes. Anti-HLA-Dr monoclonal antibodies inhibited the immune response to those antigens of high respondersin vitro, but anti-HLA-DQ monoclonal antibodies did not. On the other hand, anti-HLA-DQ monoclonal antibodies restored the immune response in low responders. Therefore, it is suggested thatHLA-DR upregulates immune response and thatHLA-DQ downregulates it and thatHLA-DQ is epistatic toHLA-DR in the regulation of immune response in humans. Furthermore, direct evidence for the differential in immune regulation betweenHLA-DR andDQ was obtained by analyzing the SCW specific T cell lines from low responders. SCW specific and HLA-DQ restricted CD4+ T cell lines could activate CD8+ suppressor T cells which in turn downregulate SCW specific CD4+ T cells whereas SCW specific and HLA-DR restricted CD4+ T cell lines could not activate CD8+ suppressor T cells. All these observation clearly demonstrated that theHLA-linkedimmune suppression genes exist in humans to control low response to natural antigens.

Download PDF

References

  • Auffray, C., Lillie, J.W., Arnot, D., Grossberger, D., Kappes, D. and Strominger, J.L. 1984. Isotypic and allotypic variation of human class II histocompatibility antigen a-chain genes,Nature 308: 327–333.

    CAS  Article  PubMed  Google Scholar 

  • Benacerraf, B. and McDevitt, H.O. 1972. Histocompatibility-linked immune response genes.Science 175: 273–279.

    CAS  Article  PubMed  Google Scholar 

  • Boss, J.M. and Strominger, J.L. 1984. Cloning and sequence analysis of the human major histocompatibility complex gene DC-3b.Proc. Natl. Acad. Sci. U.S.A. 81: 5199–5203.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Buus, S., Sette, A., Colon, S.M., Jenis, D.M. and Grey, H.M. 1986. Isolation and characterization of antigen-1a complexes involved in T cell recognition.Cell 47: 1071–1077.

    CAS  Article  PubMed  Google Scholar 

  • Ceppellini, R., Frumento, G., Ferrara, G.B., Tosi, R., Chersi, A. and Pernis, B. 1989. Binding of labelled influenza matrix peptide to HLA DR in living B lymphoid cells.Nature 339: 392–394.

    CAS  Article  PubMed  Google Scholar 

  • Fujisawa, K., Kamikawaji, N., Yasunami, M., Kimura, A., Nishimura, Y. and Sasazuki, T. Evidence for the high frequency of T cells reactive to autologous or allogeneic HLA-DQ molecules expressed on mouse L cell transfectants. submitted.

  • Hirayama, K., Nishimura, Y., Tsukamoto, K. and Sasazuki, T. 1986. Functional and molecular analysis of three distinct HLA-DR4 b-chains responsible for the MLR between HLA-Dw4, Dw15 and DKT2.J. Immunol. 137: 924–933.

    CAS  PubMed  Google Scholar 

  • Hirayama, K., Matsushita, S., Kikuchi, I., Iuchi, M., Ohta, N. and Sasazuki, T. 1987. HLA-DQ is epistatic to HLA-DR in controlling the immune response to schistosomal antigen in humans.Nature 327: 326–330.

    Article  Google Scholar 

  • Kikuchi, I., Ozawa, T., Hirayama, K. and Sasazuki, T. 1986. An HLA-linked gene controls susceptibility to lepromatous leprosy through T cell regulation.Leprocy Rev. 57, suppl. 2: 139–142.

    Google Scholar 

  • Kisielow, P., Blüthmann, H., Staerz, U.D., Steinmetz, M. and Boehmer, H.V. 1988. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes.Nature 333: 742–746.

    CAS  Article  PubMed  Google Scholar 

  • Larhammar, D., Hyldig-Nielson, J.J., Servenius, B., Anderson, G., Rask, L. and Peterson, P.A. 1983. Exon-intron organization and complete nucleotide sequence of a human major histocompatibility antigen DCb gene.Proc. Natl. Acad. Sci. U.S.A. 80: 7313–7317.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Long, E.O., Gorski, J. and Mach, B. 1984. Structural relationship of the SB beta-chain gene to HLA-D-region genes and murine I-region genes.Nature 310: 233–235.

    CAS  Article  PubMed  Google Scholar 

  • Marrack, P., Lo, D., Brinster, R., Palmiter, R., Burkly, L., Flavell, R.H. and Kappler, J. 1988. The effect of thymus environment on T cell development and tolerance.Cell 53: 627–634.

    CAS  Article  PubMed  Google Scholar 

  • Matsushita, S., Muto, M., Suemura, M., Saito, Y. and Sasazuki, T. 1987. HLA-linked nonresponsiveness to cryptomeria Japonica pollen antigen. I. Nonresponsiveness is mediated by antigen-specific suppressor T cell.J. Immunol. 138: 109–115.

    CAS  PubMed  Google Scholar 

  • McDevitt, H.O., Deak, B.D., Shreffler, D.C., Klein, J., Stimpfling, J.H. and Snell, G.D. 1972. Genetic control of the immune response. Mapping of the Ir-1 locus.J. Exp. Med. 135: 1259–1278.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Nishimura, Y. and Sasazuki, T. 1983. Suppressor T cells control the HLA-linked low responsiveness to streptococcal antigen in man.Nature 302: 67–69.

    CAS  Article  PubMed  Google Scholar 

  • Ohta, N., Nishimura, Y.K., Iuchi, M. and Sasazuki, T. 1982. Immunogenetic analysis of patients with post-schistosomal liver cirrhosis in man.Clin. Exp. Immunol. 49: 493–499.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ohta, N., Minai, M. and Sasazuki, T. 1983. Antigen-specific suppressor T lymphocytes (Leu-2a+ 3a−) in humanSchistosomiasis japonica.J. Immunol. 131: 2524–2528.

    CAS  PubMed  Google Scholar 

  • Ratnofsky, S.E., Peterson, A., Greenstein, J.L., Burakoff, S.J. 1987. Expression and function of CD8 in a murine T cell hybridoma.J. Exp. Med. 166: 1747–1757.

    CAS  Article  PubMed  Google Scholar 

  • Sasazuki, T., Kohno, Y., Iwamoto, I., Tanimura, M. and Naito, S. 1978. Association between an HLA haplotype and low responsiveness to tetanus toxid in man.Nature 272: 359–361.

    CAS  Article  PubMed  Google Scholar 

  • Sasazuki, T., Kaneoka, H., Nishimura, Y., Kaneoka, R., Hayama, M. and Ohkuni, H. 1980a. An HLA-linked immune suppression gene in man.J. Exp. Med. 152: 297s-313s.

    CAS  PubMed  Google Scholar 

  • Sasazuki, T., Ohta, N., Kaneoka, R. and Kojima, S. 1980b. Association between an HLA haplotype and low responsiveness to schistosomal worm antigen in man.J. Exp. Med. 152: 314s-318s.

    CAS  PubMed  Google Scholar 

  • Sasazuki, T., Nishimura, Y., Muto, M. and Ohta, N. 1983. HLA-linked genes controlling the immune response and disease susceptibility.Immunol. Rev. 70: 51–75.

    CAS  Article  PubMed  Google Scholar 

  • Sone, T., Tsukamoto, K., Hirayama, K., Nishimura, Y., Takenouchi, T., Aizawa, M. and Sasazuki, T. 1985. Two distinct class II molecules encoded by the genes within HLA-DR subregion of HLA-Dw2 and Dw12 can act as stimulating and restriction molecules.J. Immunol. 135: 1288–1298.

    CAS  PubMed  Google Scholar 

  • Thomson, G. and Bodmer, W. 1977. The genetic analysis of HLA and disease. InHLA and Disease, Dausset, J. and Svejgaard, A., eds., pp. 84–93, Munksgaad, Copenhagen.

    Google Scholar 

  • Tsukamoto, K., Yasunami, M., Kimura, A., Inoko, H., Ando, A., Hirose, T., Inayama, S. and Sasazuki, T. 1987. DQw1 gene from HLA-DR2-Dw12 consists of six exons and expresses multiple DQw1 polypeptide through alternative splicing.Immunogenetics 25: 343–346.

    CAS  Article  PubMed  Google Scholar 

  • Watanabe, H., Matsushita, S., Kamikawaji, N., Hirayama, K., Okumura, M. and Sasazuki, T. 1988. Immune suppression gene on HLA-Dw54-DR4-DRw53 haplotype controls nonresponsiveness in humans to hepatitis B surface antigenvia CD8+ suppressor T cells.Hum. Immunol. 22: 9–17.

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

  1. Department of Genetics, Medical Institute of Bioregulation, Kyushu University, Maidashi, Higashi-ku, 812, Fukuoka, Japan

    Takehiko Sasazuki

Authors
  1. Takehiko Sasazuki
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sasazuki, T. HLA-linkedImmune suppression genes . Jap J Human Genet 35, 1–13 (1990). https://doi.org/10.1007/BF01883163

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01883163

Key Words

  • immunogenetics
  • HLA
  • immune response gene
  • immune suppression gene
  • suppressor T cell

Further reading

Search

Advanced search

Quick links