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.
Similar content being viewed by others
Article 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.
Benacerraf, B. and McDevitt, H.O. 1972. Histocompatibility-linked immune response genes.Science 175: 273–279.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Nishimura, Y. and Sasazuki, T. 1983. Suppressor T cells control the HLA-linked low responsiveness to streptococcal antigen in man.Nature 302: 67–69.
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.
Ohta, N., Minai, M. and Sasazuki, T. 1983. Antigen-specific suppressor T lymphocytes (Leu-2a+ 3a−) in humanSchistosomiasis japonica.J. Immunol. 131: 2524–2528.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Rights 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
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF01883163
Key Words
This article is cited by
-
Identification of an HLA-DQ6-derived peptide recognized by mouse MHC class I H-2Db-restricted CD8+ T cells in HLA-DQ6 transgenic mice
Japanese Journal of Human Genetics (1997)