Skip to main content
NCBI home page
Infection and Immunity logoLink to Infection and Immunity
. 1997 Jun;65(6):2000–2005. doi: 10.1128/iai.65.6.2000-2005.1997

Functional analysis of Mycoplasma arthritidis-derived mitogen interactions with class II molecules.

C Bernatchez 1, R Al-Daccak 1, P E Mayer 1, K Mehindate 1, L Rink 1, S Mecheri 1, W Mourad 1
PMCID: PMC175276  PMID: 9169724

Abstract

The ability of superantigens (SAGs) to trigger various cellular events via major histocompatibility complex (MHC) class II molecules is largely mediated by their mode of interaction. Having two MHC class II binding sites, staphylococcal enterotoxin A (SEA) is able to dimerize MHC class II molecules on the cell surface and consequently induces cytokine gene expression in human monocytes. In contrast, cross-linking with specific monoclonal antibodies or T-cell receptor is required for staphylococcal enterotoxin B (SEB) and toxic shock syndrome toxin 1 (TSST-1) to induce similar responses. In the present study, we report how Mycoplasma arthritidis-derived mitogen (MAM) may interact with MHC class II molecules to induce cytokine gene expression in human monocytes. The data presented indicate that MAM-induced cytokine gene expression in human monocytes is Zn2+ dependent. The MAM-induced response is completely abolished by pretreatment with SEA mutants that have lost their capacity to bind either the MHC class II alpha or beta chain, with wild-type SEB, or with wild-type TSST-1, suggesting that MAM induces cytokine gene expression most probably by inducing dimerization of class II molecules. In addition, it seems that SEA and MAM interact with the same or overlapping binding sites on the MHC class II beta chain and, on the other hand, that they bind to the alpha chain most probably through the regions that are involved in SEB and TSST-1 binding.

Full Text

The Full Text of this article is available as a PDF (404.3 KB).

Selected References

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

  1. Abrahmsén L., Dohlsten M., Segrén S., Björk P., Jonsson E., Kalland T. Characterization of two distinct MHC class II binding sites in the superantigen staphylococcal enterotoxin A. EMBO J. 1995 Jul 3;14(13):2978–2986. doi: 10.1002/j.1460-2075.1995.tb07300.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Atkin C. L., Wei S., Cole B. C. The Mycoplasma arthritidis superantigen MAM: purification and identification of an active peptide. Infect Immun. 1994 Dec;62(12):5367–5375. doi: 10.1128/iai.62.12.5367-5375.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baccala R., Smith L. R., Vestberg M., Peterson P. A., Cole B. C., Theofilopoulos A. N. Mycoplasma arthritidis mitogen. V beta engaged in mice, rats, and humans, and requirement of HLA-DR alpha for presentation. Arthritis Rheum. 1992 Apr;35(4):434–442. doi: 10.1002/art.1780350413. [DOI] [PubMed] [Google Scholar]
  4. Beutner U., Frankel W. N., Cote M. S., Coffin J. M., Huber B. T. Mls-1 is encoded by the long terminal repeat open reading frame of the mouse mammary tumor provirus Mtv-7. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5432–5436. doi: 10.1073/pnas.89.12.5432. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chintagumpala M. M., Mollick J. A., Rich R. R. Staphylococcal toxins bind to different sites on HLA-DR. J Immunol. 1991 Dec 1;147(11):3876–3881. [PubMed] [Google Scholar]
  6. Cole B. C., Atkin C. L. The Mycoplasma arthritidis T-cell mitogen, MAM: a model superantigen. Immunol Today. 1991 Aug;12(8):271–276. doi: 10.1016/0167-5699(91)90125-D. [DOI] [PubMed] [Google Scholar]
  7. Cole B. C., Balderas R. A., Ahmed E. A., Kono D., Theofilopoulos A. N. Genomic composition and allelic polymorphisms influence V beta usage by the Mycoplasma arthritidis superantigen. J Immunol. 1993 Apr 15;150(8 Pt 1):3291–3299. [PubMed] [Google Scholar]
  8. Cole B. C., David C. S., Lynch D. H., Kartchner D. R. The use of transfected fibroblasts and transgenic mice establishes that stimulation of T cells by the Mycoplasma arthritidis mitogen is mediated by E alpha. J Immunol. 1990 Jan 15;144(2):420–424. [PubMed] [Google Scholar]
  9. Cole B. C., Daynes R. A., Ward J. R. Stimulation of mouse lymphocytes by a mitogen derived from Mycoplasma arthritidis. I. Transformation is associated with an H-2-linked gene that maps to the I-E/I-C subregion. J Immunol. 1981 Nov;127(5):1931–1936. [PubMed] [Google Scholar]
  10. Cole B. C., Knudtson K. L., Oliphant A., Sawitzke A. D., Pole A., Manohar M., Benson L. S., Ahmed E., Atkin C. L. The sequence of the Mycoplasma arthritidis superantigen, MAM: identification of functional domains and comparison with microbial superantigens and plant lectin mitogens. J Exp Med. 1996 Mar 1;183(3):1105–1110. doi: 10.1084/jem.183.3.1105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Crow M. K., Zagon G., Chu Z., Ravina B., Tumang J. R., Cole B. C., Friedman S. M. Human B cell differentiation induced by microbial superantigens: unselected peripheral blood lymphocytes secrete polyclonal immunoglobulin in response to Mycoplasma arthritidis mitogen. Autoimmunity. 1992;14(1):23–32. doi: 10.3109/08916939309077353. [DOI] [PubMed] [Google Scholar]
  12. Cullen C. M., Blanco L. R., Bonventre P. F., Choi E. A toxic shock syndrome toxin 1 mutant that defines a functional site critical for T-cell activation. Infect Immun. 1995 Jun;63(6):2141–2146. doi: 10.1128/iai.63.6.2141-2146.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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]
  14. Driessen C., Hirv K., Kirchner H., Rink L. Zinc regulates cytokine induction by superantigens and lipopolysaccharide. Immunology. 1995 Feb;84(2):272–277. [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Fraser J. D., Urban R. G., Strominger J. L., Robinson H. Zinc regulates the function of two superantigens. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5507–5511. doi: 10.1073/pnas.89.12.5507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Heldin C. H. Dimerization of cell surface receptors in signal transduction. Cell. 1995 Jan 27;80(2):213–223. doi: 10.1016/0092-8674(95)90404-2. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Hudson K. R., Tiedemann R. E., Urban R. G., Lowe S. C., Strominger J. L., Fraser J. D. Staphylococcal enterotoxin A has two cooperative binding sites on major histocompatibility complex class II. J Exp Med. 1995 Sep 1;182(3):711–720. doi: 10.1084/jem.182.3.711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jardetzky T. S., Brown J. H., Gorga J. C., Stern L. J., Urban R. G., Chi Y. I., Stauffacher C., Strominger J. L., Wiley D. C. Three-dimensional structure of a human class II histocompatibility molecule complexed with superantigen. Nature. 1994 Apr 21;368(6473):711–718. doi: 10.1038/368711a0. [DOI] [PubMed] [Google Scholar]
  21. Kappler J. W., Herman A., Clements J., Marrack P. Mutations defining functional regions of the superantigen staphylococcal enterotoxin B. J Exp Med. 1992 Feb 1;175(2):387–396. doi: 10.1084/jem.175.2.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Karp D. R., Long E. O. Identification of HLA-DR1 beta chain residues critical for binding staphylococcal enterotoxins A and E. J Exp Med. 1992 Feb 1;175(2):415–424. doi: 10.1084/jem.175.2.415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kim J., Urban R. G., Strominger J. L., Wiley D. C. Toxic shock syndrome toxin-1 complexed with a class II major histocompatibility molecule HLA-DR1. Science. 1994 Dec 16;266(5192):1870–1874. doi: 10.1126/science.7997880. [DOI] [PubMed] [Google Scholar]
  24. Kozono H., Parker D., White J., Marrack P., Kappler J. Multiple binding sites for bacterial superantigens on soluble class II MHC molecules. Immunity. 1995 Aug;3(2):187–196. doi: 10.1016/1074-7613(95)90088-8. [DOI] [PubMed] [Google Scholar]
  25. Mahana W., al-Daccak R., Lévéillé C., Valet J. P., Hébert J., Ouellette M., Mourad W. A natural mutation of the amino acid residue at position 60 destroys staphylococcal enterotoxin A murine T-cell mitogenicity. Infect Immun. 1995 Aug;63(8):2826–2832. doi: 10.1128/iai.63.8.2826-2832.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mehindate K., Thibodeau J., Dohlsten M., Kalland T., Sékaly R. P., Mourad W. Cross-linking of major histocompatibility complex class II molecules by staphylococcal enterotoxin A superantigen is a requirement for inflammatory cytokine gene expression. J Exp Med. 1995 Nov 1;182(5):1573–1577. doi: 10.1084/jem.182.5.1573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Mehindate K., al-Daccak R., Damdoumi F., Mourad W. Synergistic effect between CD40 and class II signals overcome the requirement for class II dimerization in superantigen-induced cytokine gene expression. Eur J Immunol. 1996 Sep;26(9):2075–2080. doi: 10.1002/eji.1830260917. [DOI] [PubMed] [Google Scholar]
  28. Rink L., Nicklas W., Luhm J., Kruse R., Kirchner H. Induction of a proinflammatory cytokine network by Mycoplasma arthritidis-derived superantigen (MAS). J Interferon Cytokine Res. 1996 Oct;16(10):861–868. doi: 10.1089/jir.1996.16.861. [DOI] [PubMed] [Google Scholar]
  29. Schad E. M., Zaitseva I., Zaitsev V. N., Dohlsten M., Kalland T., Schlievert P. M., Ohlendorf D. H., Svensson L. A. Crystal structure of the superantigen staphylococcal enterotoxin type A. EMBO J. 1995 Jul 17;14(14):3292–3301. doi: 10.1002/j.1460-2075.1995.tb07336.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Scherer M. T., Ignatowicz L., Winslow G. M., Kappler J. W., Marrack P. Superantigens: bacterial and viral proteins that manipulate the immune system. Annu Rev Cell Biol. 1993;9:101–128. doi: 10.1146/annurev.cb.09.110193.000533. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Sundström M., Abrahmsén L., Antonsson P., Mehindate K., Mourad W., Dohlsten M. The crystal structure of staphylococcal enterotoxin type D reveals Zn2+-mediated homodimerization. EMBO J. 1996 Dec 16;15(24):6832–6840. [PMC free article] [PubMed] [Google Scholar]
  33. Thibodeau J., Cloutier I., Lavoie P. M., Labrecque N., Mourad W., Jardetzky T., Sékaly R. P. Subsets of HLA-DR1 molecules defined by SEB and TSST-1 binding. Science. 1994 Dec 16;266(5192):1874–1878. doi: 10.1126/science.7997881. [DOI] [PubMed] [Google Scholar]
  34. Tiedemann R. E., Fraser J. D. Cross-linking of MHC class II molecules by staphylococcal enterotoxin A is essential for antigen-presenting cell and T cell activation. J Immunol. 1996 Nov 1;157(9):3958–3966. [PubMed] [Google Scholar]
  35. Torres B. A., Griggs N. D., Johnson H. M. Bacterial and retroviral superantigens share a common binding region on class II MHC antigens. Nature. 1993 Jul 8;364(6433):152–154. doi: 10.1038/364152a0. [DOI] [PubMed] [Google Scholar]
  36. Trede N. S., Geha R. S., Chatila T. Transcriptional activation of IL-1 beta and tumor necrosis factor-alpha genes by MHC class II ligands. J Immunol. 1991 Apr 1;146(7):2310–2315. [PubMed] [Google Scholar]
  37. Ulrich R. G., Bavari S., Olson M. A. Staphylococcal enterotoxins A and B share a common structural motif for binding class II major histocompatibility complex molecules. Nat Struct Biol. 1995 Jul;2(7):554–560. doi: 10.1038/nsb0795-554. [DOI] [PubMed] [Google Scholar]
  38. Yunis J. J., Band H., Bonneville F., Yunis E. J. Differential expression of MHC class II antigens in myelomonocytic leukemia cell lines. Blood. 1989 Mar;73(4):931–937. [PubMed] [Google Scholar]
  39. al-Daccak R., Mehindate K., Hébert J., Rink L., Mecheri S., Mourad W. Mycoplasma arthritidis-derived superantigen induces proinflammatory monokine gene expression in the THP-1 human monocytic cell line. Infect Immun. 1994 Jun;62(6):2409–2416. doi: 10.1128/iai.62.6.2409-2416.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. al-Daccak R., Mehindate K., Poubelle P. E., Mourad W. Signalling via MHC class II molecules selectively induces IL-1 beta over IL-1 receptor antagonist gene expression. Biochem Biophys Res Commun. 1994 Jun 15;201(2):855–860. doi: 10.1006/bbrc.1994.1779. [DOI] [PubMed] [Google Scholar]
  41. von Bonin A., Ehrlich S., Malcherek G., Fleischer B. Major histocompatibility complex class II-associated peptides determine the binding of the superantigen toxic shock syndrome toxin-1. Eur J Immunol. 1995 Oct;25(10):2894–2898. doi: 10.1002/eji.1830251028. [DOI] [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES