Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1992 Feb 1;175(2):415–424. doi: 10.1084/jem.175.2.415

Identification of HLA-DR1 beta chain residues critical for binding staphylococcal enterotoxins A and E

PMCID: PMC2119122  PMID: 1370684

Abstract

Superantigens are thought to make external contacts with major histocompatibility complex (MHC) class II molecules and with the V beta portion of a T cell antigen receptor (TCR), thereby stimulating entire families of T cells. The precise mapping of superantigen binding sites on class II molecules may provide valuable information on how TCR and MHC molecules interact. Two bacterial superantigens, staphylococcal enterotoxins A and E (SEA/SEE) bind well to most HLA-DR alleles, but poorly to HLA-DRw53. The sequences responsible for this binding were localized to the putative alpha helix of the DR beta chain by measuring toxin binding to a panel of chimeric class II molecules expressed on transfected cells. Binding of SEA/SEE to the DRw14 (Dw9) molecule suggested that the conserved histidine 81 in the beta chain of most DR molecules was important, whereas the tyrosine 81 in the DRw53 beta chain was detrimental for high-affinity binding. To prove this, reciprocal point mutations were introduced in the DR1 and DRw53 beta chains. Mutation of histidine 81 in the DR1 beta chain to tyrosine reduced SEA/SEE binding, but did not prevent recognition of two DR1- restricted peptides by six of eight antigen-specific T cell lines. Conversely, introduction to histidine at position 81 in the DRw53 beta chain restored normal levels of SEA/SEE binding. These data suggest that a binding site of SEA and SEE lies on the outer face of the beta chain alpha helix, pointing away from the antigen-binding groove.

Full Text

The Full Text of this article is available as a PDF (975.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Betley M. J., Mekalanos J. J. Nucleotide sequence of the type A staphylococcal enterotoxin gene. J Bacteriol. 1988 Jan;170(1):34–41. doi: 10.1128/jb.170.1.34-41.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brown J. H., Jardetzky T., Saper M. A., Samraoui B., Bjorkman P. J., Wiley D. C. A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature. 1988 Apr 28;332(6167):845–850. doi: 10.1038/332845a0. [DOI] [PubMed] [Google Scholar]
  3. Choi Y. W., Herman A., DiGiusto D., Wade T., Marrack P., Kappler J. Residues of the variable region of the T-cell-receptor beta-chain that interact with S. aureus toxin superantigens. Nature. 1990 Aug 2;346(6283):471–473. doi: 10.1038/346471a0. [DOI] [PubMed] [Google Scholar]
  4. Choi Y. W., Kotzin B., Herron L., Callahan J., Marrack P., Kappler J. Interaction of Staphylococcus aureus toxin "superantigens" with human T cells. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8941–8945. doi: 10.1073/pnas.86.22.8941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. 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]
  6. Chou P. Y., Fasman G. D. Empirical predictions of protein conformation. Annu Rev Biochem. 1978;47:251–276. doi: 10.1146/annurev.bi.47.070178.001343. [DOI] [PubMed] [Google Scholar]
  7. Cole B. C., Kartchner D. R., Wells D. J. Stimulation of mouse lymphocytes by a mitogen derived from Mycoplasma arthritidis (MAM). VIII. Selective activation of T cells expressing distinct V beta T cell receptors from various strains of mice by the "superantigen" MAM. J Immunol. 1990 Jan 15;144(2):425–431. [PubMed] [Google Scholar]
  8. Couch J. L., Soltis M. T., Betley M. J. Cloning and nucleotide sequence of the type E staphylococcal enterotoxin gene. J Bacteriol. 1988 Jul;170(7):2954–2960. doi: 10.1128/jb.170.7.2954-2960.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Davis L. S., Wacholtz M. C., Lipsky P. E. The induction of T cell unresponsiveness by rapidly modulating CD3. J Immunol. 1989 Feb 15;142(4):1084–1094. [PubMed] [Google Scholar]
  10. Davis M. M., Bjorkman P. J. T-cell antigen receptor genes and T-cell recognition. Nature. 1988 Aug 4;334(6181):395–402. doi: 10.1038/334395a0. [DOI] [PubMed] [Google Scholar]
  11. Dellabona P., Peccoud J., Kappler J., Marrack P., Benoist C., Mathis D. Superantigens interact with MHC class II molecules outside of the antigen groove. Cell. 1990 Sep 21;62(6):1115–1121. doi: 10.1016/0092-8674(90)90388-u. [DOI] [PubMed] [Google Scholar]
  12. Estess P., Begovich A. B., Koo M., Jones P. P., McDevitt H. O. Sequence analysis and structure-function correlations of murine q, k, u, s, and f haplotype I-A beta cDNA clones. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3594–3598. doi: 10.1073/pnas.83.11.3594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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]
  14. Fraser J. D. High-affinity binding of staphylococcal enterotoxins A and B to HLA-DR. Nature. 1989 May 18;339(6221):221–223. doi: 10.1038/339221a0. [DOI] [PubMed] [Google Scholar]
  15. Garnier J., Osguthorpe D. J., Robson B. Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J Mol Biol. 1978 Mar 25;120(1):97–120. doi: 10.1016/0022-2836(78)90297-8. [DOI] [PubMed] [Google Scholar]
  16. Gorski J. First domain sequence of the HLA-DRB1 chain from two HLA-DRw14 homozygous typing cell lines: TEM (Dw9) and AMALA (Dw16). Hum Immunol. 1989 Feb;24(2):145–149. doi: 10.1016/0198-8859(89)90054-2. [DOI] [PubMed] [Google Scholar]
  17. Goyert S. M., Silver J. Further characterization of HLA-DS molecules: implications for studies assessing the role of human Ia molecules in cell interactions and disease susceptibility. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5719–5723. doi: 10.1073/pnas.80.18.5719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Herman A., Croteau G., Sekaly R. P., Kappler J., Marrack P. HLA-DR alleles differ in their ability to present staphylococcal enterotoxins to T cells. J Exp Med. 1990 Sep 1;172(3):709–717. doi: 10.1084/jem.172.3.709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Herman A., Labrecque N., Thibodeau J., Marrack P., Kappler J. W., Sekaly R. P. Identification of the staphylococcal enterotoxin A superantigen binding site in the beta 1 domain of the human histocompatibility antigen HLA-DR. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):9954–9958. doi: 10.1073/pnas.88.22.9954. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Jacobson S., Sekaly R. P., Jacobson C. L., McFarland H. F., Long E. O. HLA class II-restricted presentation of cytoplasmic measles virus antigens to cytotoxic T cells. J Virol. 1989 Apr;63(4):1756–1762. doi: 10.1128/jvi.63.4.1756-1762.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Janeway C. A., Jr, Carding S., Jones B., Murray J., Portoles P., Rasmussen R., Rojo J., Saizawa K., West J., Bottomly K. CD4+ T cells: specificity and function. Immunol Rev. 1988 Jan;101:39–80. doi: 10.1111/j.1600-065x.1988.tb00732.x. [DOI] [PubMed] [Google Scholar]
  23. Janeway C. A., Jr Self superantigens? Cell. 1990 Nov 16;63(4):659–661. doi: 10.1016/0092-8674(90)90130-7. [DOI] [PubMed] [Google Scholar]
  24. Janeway C. A., Jr, Yagi J., Conrad P. J., Katz M. E., Jones B., Vroegop S., Buxser S. T-cell responses to Mls and to bacterial proteins that mimic its behavior. Immunol Rev. 1989 Feb;107:61–88. doi: 10.1111/j.1600-065x.1989.tb00003.x. [DOI] [PubMed] [Google Scholar]
  25. Kavathas P., Bach F. H., DeMars R. Gamma ray-induced loss of expression of HLA and glyoxalase I alleles in lymphoblastoid cells. Proc Natl Acad Sci U S A. 1980 Jul;77(7):4251–4255. doi: 10.1073/pnas.77.7.4251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. 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]
  28. Mollick J. A., Chintagumpala M., Cook R. G., Rich R. R. Staphylococcal exotoxin activation of T cells. Role of exotoxin-MHC class II binding affinity and class II isotype. J Immunol. 1991 Jan 15;146(2):463–468. [PubMed] [Google Scholar]
  29. Mollick J. A., Cook R. G., Rich R. R. Class II MHC molecules are specific receptors for staphylococcus enterotoxin A. Science. 1989 May 19;244(4906):817–820. doi: 10.1126/science.2658055. [DOI] [PubMed] [Google Scholar]
  31. Pontzer C. H., Russell J. K., Johnson H. M. Structural basis for differential binding of staphylococcal enterotoxin A and toxic shock syndrome toxin 1 to class II major histocompatibility molecules. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):125–128. doi: 10.1073/pnas.88.1.125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Scholl P. R., Diez A., Geha R. S. Staphylococcal enterotoxin B and toxic shock syndrome toxin-1 bind to distinct sites on HLA-DR and HLA-DQ molecules. J Immunol. 1989 Oct 15;143(8):2583–2588. [PubMed] [Google Scholar]
  33. Scholl P. R., Sekaly R. P., Diez A., Glimcher L. H., Geha R. S. Binding of toxic shock syndrome toxin-1 to murine major histocompatibility complex class II molecules. Eur J Immunol. 1990 Sep;20(9):1911–1916. doi: 10.1002/eji.1830200907. [DOI] [PubMed] [Google Scholar]
  34. Scholl P., Diez A., Mourad W., Parsonnet J., Geha R. S., Chatila T. Toxic shock syndrome toxin 1 binds to major histocompatibility complex class II molecules. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4210–4214. doi: 10.1073/pnas.86.11.4210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Shaw S., Ziegler A., DeMars R. Specificity of monoclonal antibodies directed against human and murine class II histocompatibility antigens as analyzed by binding to HLA-deletion mutant cell lines. Hum Immunol. 1985 Apr;12(4):191–211. doi: 10.1016/0198-8859(85)90336-2. [DOI] [PubMed] [Google Scholar]
  36. Singh B. R., Betley M. J. Comparative structural analysis of staphylococcal enterotoxins A and E. J Biol Chem. 1989 Mar 15;264(8):4404–4411. [PubMed] [Google Scholar]
  37. Tomai M., Kotb M., Majumdar G., Beachey E. H. Superantigenicity of streptococcal M protein. J Exp Med. 1990 Jul 1;172(1):359–362. doi: 10.1084/jem.172.1.359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Trowsdale J., Young J. A., Kelly A. P., Austin P. J., Carson S., Meunier H., So A., Erlich H. A., Spielman R. S., Bodmer J. Structure, sequence and polymorphism in the HLA-D region. Immunol Rev. 1985 Jul;85:5–43. doi: 10.1111/j.1600-065x.1985.tb01129.x. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. 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]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES