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. 1994 Jan;62(1):135–144. doi: 10.1128/iai.62.1.135-144.1994

Human T-cell responses to Mycoplasma arthritidis-derived superantigen.

N Bhardwaj 1, A S Hodtsev 1, A Nisanian 1, S Kabak 1, S M Friedman 1, B C Cole 1, D N Posnett 1
PMCID: PMC186078  PMID: 8262619

Abstract

When injected into mice, Mycoplasma arthritidis causes a chronic arthritis that resembles rheumatoid arthritis, histologically. The organism produces a superantigen termed Mycoplasma arthritidis mitogen or MAM, that in humans preferentially expands T cells whose antigen receptors express V beta 17. T cells with this phenotype appear to be increased in rheumatoid synovial effusions. We describe a novel approach to isolating and characterizing human MAM-reactive T-cell lines and determining their T-cell receptor (TCR) V beta usage. Lines were prepared from T cells that clustered with dendritic cells during a 2-day exposure to MAM. Cluster and noncluster fractions of T cells were then expanded by using feeder cells and a polyclonal mitogen. Most of the MAM reactivity was found in dendritic T-cell clusters, as were most of the T cells expressing TCR V beta 17. After expansion, 76% of the cluster-derived T-cell lines were MAM reactive, while no reactivity was seen in cell lines derived from the noncluster fraction. Of the MAM-reactive lines, 49% expressed V beta 17 on some or all of the cells. Cell lines from both cluster and noncluster fractions were analyzed for TCR V beta mRNA expression by PCR amplification. Other V beta genes (5.1, 7, 8, 12, and 20) were found to be expressed by lines that were MAM reactive, although these were not a major component of the cluster-derived T cells. Some non-cluster-derived lines expressed V beta s 17, 12, and 7, but these proved to be nonreactive to MAM. Therefore, dendritic cells can be used to immunoselect and characterize T cells that express superantigen-reactive TCRs.

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Selected References

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  1. Acuto O., Campen T. J., Royer H. D., Hussey R. E., Poole C. B., Reinherz E. L. Molecular analysis of T cell receptor (Ti) variable region (V) gene expression. Evidence that a single Ti beta V gene family can be used in formation of V domains on phenotypically and functionally diverse T cell populations. J Exp Med. 1985 Jun 1;161(6):1326–1343. doi: 10.1084/jem.161.6.1326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Atkin C. L., Cole B. C., Sullivan G. J., Washburn L. R., Wiley B. B. Stimulation of mouse lymphocytes by a mitogen derived from Mycoplasma arthritidis. V. A small basic protein from culture supernatants is a potent T cell mitogen. J Immunol. 1986 Sep 1;137(5):1581–1589. [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. Bhardwaj N., Friedman S. M., Cole B. C., Nisanian A. J. Dendritic cells are potent antigen-presenting cells for microbial superantigens. J Exp Med. 1992 Jan 1;175(1):267–273. doi: 10.1084/jem.175.1.267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bhardwaj N., Lau L. L., Rivelis M., Steinman R. M. Interleukin-1 production by mononuclear cells from rheumatoid synovial effusions. Cell Immunol. 1988 Jul;114(2):405–423. doi: 10.1016/0008-8749(88)90332-2. [DOI] [PubMed] [Google Scholar]
  6. Bhardwaj N., Santhanam U., Lau L. L., Tatter S. B., Ghrayeb J., Rivelis M., Steinman R. M., Sehgal P. B., May L. T. IL-6/IFN-beta 2 in synovial effusions of patients with rheumatoid arthritis and other arthritides. Identification of several isoforms and studies of cellular sources. J Immunol. 1989 Oct 1;143(7):2153–2159. [PubMed] [Google Scholar]
  7. Bhardwaj N., Young J. W., Nisanian A. J., Baggers J., Steinman R. M. Small amounts of superantigen, when presented on dendritic cells, are sufficient to initiate T cell responses. J Exp Med. 1993 Aug 1;178(2):633–642. doi: 10.1084/jem.178.2.633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bigler R. D., Fisher D. E., Wang C. Y., Rinnooy Kan E. A., Kunkel H. G. Idiotype-like molecules on cells of a human T cell leukemia. J Exp Med. 1983 Sep 1;158(3):1000–1005. doi: 10.1084/jem.158.3.1000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. 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]
  12. Cole B. C., Griffiths M. M. Triggering and exacerbation of autoimmune arthritis by the Mycoplasma arthritidis superantigen MAM. Arthritis Rheum. 1993 Jul;36(7):994–1002. doi: 10.1002/art.1780360717. [DOI] [PubMed] [Google Scholar]
  13. Cole B. C., Ward J. R., Jones R. S., Cahill J. F. Chronic proliferative arthritis of mice induced by Mycoplasma arthritidis. I. Induction of disease and histopathological characteristics. Infect Immun. 1971 Oct;4(4):344–355. doi: 10.1128/iai.4.4.344-355.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. Feldmann M., Basten A. Cell interactions in the immune response in vitro. 3. Specific collaboration across a cell impermeable membrane. J Exp Med. 1972 Jul 1;136(1):49–67. doi: 10.1084/jem.136.1.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Flechner E. R., Freudenthal P. S., Kaplan G., Steinman R. M. Antigen-specific T lymphocytes efficiently cluster with dendritic cells in the human primary mixed-leukocyte reaction. Cell Immunol. 1988 Jan;111(1):183–195. doi: 10.1016/0008-8749(88)90062-7. [DOI] [PubMed] [Google Scholar]
  17. Freudenthal P. S., Steinman R. M. The distinct surface of human blood dendritic cells, as observed after an improved isolation method. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7698–7702. doi: 10.1073/pnas.87.19.7698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Friedman S. M., Crow M. K., Tumang J. R., Tumang M., Xu Y. Q., Hodtsev A. S., Cole B. C., Posnett D. N. Characterization of human T cells reactive with the Mycoplasma arthritidis-derived superantigen (MAM): generation of a monoclonal antibody against V beta 17, the T cell receptor gene product expressed by a large fraction of MAM-reactive human T cells. J Exp Med. 1991 Oct 1;174(4):891–900. doi: 10.1084/jem.174.4.891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Friedman S. M., Posnett D. N., Tumang J. R., Cole B. C., Crow M. K. A potential role for microbial superantigens in the pathogenesis of systemic autoimmune disease. Arthritis Rheum. 1991 Apr;34(4):468–480. doi: 10.1002/art.1780340412. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Herman A., Kappler J. W., Marrack P., Pullen A. M. Superantigens: mechanism of T-cell stimulation and role in immune responses. Annu Rev Immunol. 1991;9:745–772. doi: 10.1146/annurev.iy.09.040191.003525. [DOI] [PubMed] [Google Scholar]
  22. Howell M. D., Diveley J. P., Lundeen K. A., Esty A., Winters S. T., Carlo D. J., Brostoff S. W. Limited T-cell receptor beta-chain heterogeneity among interleukin 2 receptor-positive synovial T cells suggests a role for superantigen in rheumatoid arthritis. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10921–10925. doi: 10.1073/pnas.88.23.10921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Inaba K., Inaba M., Naito M., Steinman R. M. Dendritic cell progenitors phagocytose particulates, including bacillus Calmette-Guerin organisms, and sensitize mice to mycobacterial antigens in vivo. J Exp Med. 1993 Aug 1;178(2):479–488. doi: 10.1084/jem.178.2.479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Inaba K., Metlay J. P., Crowley M. T., Steinman R. M. Dendritic cells pulsed with protein antigens in vitro can prime antigen-specific, MHC-restricted T cells in situ. J Exp Med. 1990 Aug 1;172(2):631–640. doi: 10.1084/jem.172.2.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Inaba K., Metlay J. P., Crowley M. T., Witmer-Pack M., Steinman R. M. Dendritic cells as antigen presenting cells in vivo. Int Rev Immunol. 1990;6(2-3):197–206. doi: 10.3109/08830189009056630. [DOI] [PubMed] [Google Scholar]
  26. Inaba M., Inaba K., Hosono M., Kumamoto T., Ishida T., Muramatsu S., Masuda T., Ikehara S. Distinct mechanisms of neonatal tolerance induced by dendritic cells and thymic B cells. J Exp Med. 1991 Mar 1;173(3):549–559. doi: 10.1084/jem.173.3.549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Li Y., Szabo P., Robinson M. A., Dong B., Posnett D. N. Allelic variations in the human T cell receptor V beta 6.7 gene products. J Exp Med. 1990 Jan 1;171(1):221–230. doi: 10.1084/jem.171.1.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Li Y., Wong A., Szabo P., Posnett D. N. Human Tcrb-V6.10 is a pseudogene with Alu repetitive sequences in the promoter region. Immunogenetics. 1993;37(5):347–355. doi: 10.1007/BF00216799. [DOI] [PubMed] [Google Scholar]
  29. Maecker H. T., Levy R. Prevalence of antigen receptor variants in human T cell lines and tumors. J Immunol. 1989 Feb 15;142(4):1395–1404. [PubMed] [Google Scholar]
  30. 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]
  31. Miethke T., Wahl C., Heeg K., Echtenacher B., Krammer P. H., Wagner H. T cell-mediated lethal shock triggered in mice by the superantigen staphylococcal enterotoxin B: critical role of tumor necrosis factor. J Exp Med. 1992 Jan 1;175(1):91–98. doi: 10.1084/jem.175.1.91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Paliard X., West S. G., Lafferty J. A., Clements J. R., Kappler J. W., Marrack P., Kotzin B. L. Evidence for the effects of a superantigen in rheumatoid arthritis. Science. 1991 Jul 19;253(5017):325–329. doi: 10.1126/science.1857971. [DOI] [PubMed] [Google Scholar]
  33. Pancholi P., Steinman R. M., Bhardwaj N. An approach to isolating T cell lines that react to antigens presented on the surface of dendritic cells. Clin Exp Immunol. 1991 Aug;85(2):349–356. doi: 10.1111/j.1365-2249.1991.tb05731.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Pancholi P., Steinman R. M., Bhardwaj N. Dendritic cells efficiently immunoselect mycobacterial-reactive T cells in human blood, including clonable antigen-reactive precursors. Immunology. 1992 Jun;76(2):217–224. [PMC free article] [PubMed] [Google Scholar]
  35. Posnett D. N. Allelic variations of human TCR V gene products. Immunol Today. 1990 Oct;11(10):368–373. doi: 10.1016/0167-5699(90)90143-w. [DOI] [PubMed] [Google Scholar]
  36. Posnett D. N., Wang C. Y., Friedman S. M. Inherited polymorphism of the human T-cell antigen receptor detected by a monoclonal antibody. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7888–7892. doi: 10.1073/pnas.83.20.7888. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Schlievert P. M., Shands K. N., Dan B. B., Schmid G. P., Nishimura R. D. Identification and characterization of an exotoxin from Staphylococcus aureus associated with toxic-shock syndrome. J Infect Dis. 1981 Apr;143(4):509–516. doi: 10.1093/infdis/143.4.509. [DOI] [PubMed] [Google Scholar]
  38. Sperber K., Shaked A., Posnett D. N., Hirschman S. Z., Bekesi G., Mayer L. Surface expression of CD-4 does not predict susceptibility to infection with HIV-1 in human monocyte hybridomas. J Clin Lab Immunol. 1990 Apr;31(4):151–156. [PubMed] [Google Scholar]
  39. Tumang J. R., Posnett D. N., Cole B. C., Crow M. K., Friedman S. M. Helper T cell-dependent human B cell differentiation mediated by a mycoplasmal superantigen bridge. J Exp Med. 1990 Jun 1;171(6):2153–2158. doi: 10.1084/jem.171.6.2153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Wang C. Y., Bushkin Y., Pica R., Lane C., McGrath H., Posnett D. N. Stimulation and expansion of a human T-cell subpopulation by a monoclonal antibody to T-cell receptor molecule. Hybridoma. 1986 Fall;5(3):179–190. doi: 10.1089/hyb.1986.5.179. [DOI] [PubMed] [Google Scholar]
  41. 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]
  42. Winslow G. M., Scherer M. T., Kappler J. W., Marrack P. Detection and biochemical characterization of the mouse mammary tumor virus 7 superantigen (Mls-1a). Cell. 1992 Nov 27;71(5):719–730. doi: 10.1016/0092-8674(92)90549-r. [DOI] [PubMed] [Google Scholar]
  43. Young J. W., Steinman R. M. Accessory cell requirements for the mixed-leukocyte reaction and polyclonal mitogens, as studied with a new technique for enriching blood dendritic cells. Cell Immunol. 1988 Jan;111(1):167–182. doi: 10.1016/0008-8749(88)90061-5. [DOI] [PubMed] [Google Scholar]
  44. Young J. W., Steinman R. M. Dendritic cells stimulate primary human cytolytic lymphocyte responses in the absence of CD4+ helper T cells. J Exp Med. 1990 Apr 1;171(4):1315–1332. doi: 10.1084/jem.171.4.1315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zvaifler N. J., Steinman R. M., Kaplan G., Lau L. L., Rivelis M. Identification of immunostimulatory dendritic cells in the synovial effusions of patients with rheumatoid arthritis. J Clin Invest. 1985 Aug;76(2):789–800. doi: 10.1172/JCI112036. [DOI] [PMC free article] [PubMed] [Google Scholar]

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