Skip to main content
Molecular Medicine logoLink to Molecular Medicine
. 1999 May;5(5):301–312.

Predominance of Vgamma9/Vdelta2 T lymphocytes in the cerebrospinal fluid of children with tuberculous meningitis: reversal after chemotherapy.

F Dieli 1, G Sireci 1, C Di Sano 1, E Champagne 1, J J Fourniè 1, J I Salerno 1
PMCID: PMC2230421  PMID: 10390546

Abstract

BACKGROUND: We analyzed the gammadelta T cell composition and responses in the peripheral blood and cerebrospinal fluid (CSF) of children affected by tuberculous meningitis (TBM) and in control children. MATERIALS AND METHODS: Peripheral blood and CSF samples were stimulated with different phosphoantigens and IL-2, and expansion of Vgamma9/Vdelta2 T cells assessed by FACS analysis. Vgamma9/Vdelta2 lines were obtained by culturing CSF or peripheral blood mononuclear cells (PBMC) in vitro with phosphoantigens and IL-2 for 2 months, and tested for proliferation and cytokine production in response to phosphoantigens. Vdelta2(D)Jdelta junctional sequence length was assessed by PCR. RESULTS: The repertoire of gammadelta T cells from the CSF of TBM patients was characterized by the predominance of Vgamma9/Vdelta2 T lymphocytes, which accounted for >80% of gammadelta T cells. Vgamma9/Vdelta2 cells from the CSF of TBM children responded to different synthetic and natural (mycobacterial) phosphoantigens and produced discrete amounts of IFN-gamma and TNF-alpha. The in vitro expansion of Vgamma9/Vdelta2 T cells from CSF and peripheral blood of TBM patients prominently decreased following chemotherapy, and similarly, the proportion of ex vivo unstimulated Vgamma9/Vdelta2 T cells in CSF of TBM patients decreased to levels detected in the CSF of control subjects. Vdelta2 CDR3 TCR analysis showed that the remaining Vdelta2 cells in the CSF of TBM patients were still polyclonal. CONCLUSIONS: These findings are consistent with an involvement of Vgamma9/Vdelta2 T cells in TBM. http://link. springer-ny.com/link/service/journals/00020/bibs/5n5p301. html

Full text

PDF
301

Images in this article

Selected References

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

  1. Balbi B., Valle M. T., Oddera S., Giunti D., Manca F., Rossi G. A., Allegra L. T-lymphocytes with gamma delta+ V delta 2+ antigen receptors are present in increased proportions in a fraction of patients with tuberculosis or with sarcoidosis. Am Rev Respir Dis. 1993 Dec;148(6 Pt 1):1685–1690. doi: 10.1164/ajrccm/148.6_Pt_1.1685. [DOI] [PubMed] [Google Scholar]
  2. Barnes P. F., Grisso C. L., Abrams J. S., Band H., Rea T. H., Modlin R. L. Gamma delta T lymphocytes in human tuberculosis. J Infect Dis. 1992 Mar;165(3):506–512. doi: 10.1093/infdis/165.3.506. [DOI] [PubMed] [Google Scholar]
  3. Behr C., Poupot R., Peyrat M. A., Poquet Y., Constant P., Dubois P., Bonneville M., Fournie J. J. Plasmodium falciparum stimuli for human gammadelta T cells are related to phosphorylated antigens of mycobacteria. Infect Immun. 1996 Aug;64(8):2892–2896. doi: 10.1128/iai.64.8.2892-2896.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bermudez L. E., Young L. S. Tumor necrosis factor, alone or in combination with IL-2, but not IFN-gamma, is associated with macrophage killing of Mycobacterium avium complex. J Immunol. 1988 May 1;140(9):3006–3013. [PubMed] [Google Scholar]
  5. Bürk M. R., Mori L., De Libero G. Human V gamma 9-V delta 2 cells are stimulated in a cross-reactive fashion by a variety of phosphorylated metabolites. Eur J Immunol. 1995 Jul;25(7):2052–2058. doi: 10.1002/eji.1830250737. [DOI] [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Constant P., Davodeau F., Peyrat M. A., Poquet Y., Puzo G., Bonneville M., Fournié J. J. Stimulation of human gamma delta T cells by nonpeptidic mycobacterial ligands. Science. 1994 Apr 8;264(5156):267–270. doi: 10.1126/science.8146660. [DOI] [PubMed] [Google Scholar]
  8. D'Souza C. D., Cooper A. M., Frank A. A., Mazzaccaro R. J., Bloom B. R., Orme I. M. An anti-inflammatory role for gamma delta T lymphocytes in acquired immunity to Mycobacterium tuberculosis. J Immunol. 1997 Feb 1;158(3):1217–1221. [PubMed] [Google Scholar]
  9. De Libero G., Casorati G., Giachino C., Carbonara C., Migone N., Matzinger P., Lanzavecchia A. Selection by two powerful antigens may account for the presence of the major population of human peripheral gamma/delta T cells. J Exp Med. 1991 Jun 1;173(6):1311–1322. doi: 10.1084/jem.173.6.1311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Falini B., Flenghi L., Pileri S., Pelicci P., Fagioli M., Martelli M. F., Moretta L., Ciccone E. Distribution of T cells bearing different forms of the T cell receptor gamma/delta in normal and pathological human tissues. J Immunol. 1989 Oct 15;143(8):2480–2488. [PubMed] [Google Scholar]
  11. Flynn J. L., Chan J., Triebold K. J., Dalton D. K., Stewart T. A., Bloom B. R. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med. 1993 Dec 1;178(6):2249–2254. doi: 10.1084/jem.178.6.2249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hirsch C. S., Hussain R., Toossi Z., Dawood G., Shahid F., Ellner J. J. Cross-modulation by transforming growth factor beta in human tuberculosis: suppression of antigen-driven blastogenesis and interferon gamma production. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3193–3198. doi: 10.1073/pnas.93.8.3193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ito M., Kojiro N., Ikeda T., Ito T., Funada J., Kokubu T. Increased proportions of peripheral blood gamma delta T cells in patients with pulmonary tuberculosis. Chest. 1992 Jul;102(1):195–197. doi: 10.1378/chest.102.1.195. [DOI] [PubMed] [Google Scholar]
  14. Kabelitz D., Bender A., Prospero T., Wesselborg S., Janssen O., Pechhold K. The primary response of human gamma/delta + T cells to Mycobacterium tuberculosis is restricted to V gamma 9-bearing cells. J Exp Med. 1991 Jun 1;173(6):1331–1338. doi: 10.1084/jem.173.6.1331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kabelitz D., Bender A., Schondelmaier S., Schoel B., Kaufmann S. H. A large fraction of human peripheral blood gamma/delta + T cells is activated by Mycobacterium tuberculosis but not by its 65-kD heat shock protein. J Exp Med. 1990 Mar 1;171(3):667–679. doi: 10.1084/jem.171.3.667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ladel C. H., Blum C., Dreher A., Reifenberg K., Kaufmann S. H. Protective role of gamma/delta T cells and alpha/beta T cells in tuberculosis. Eur J Immunol. 1995 Oct;25(10):2877–2881. doi: 10.1002/eji.1830251025. [DOI] [PubMed] [Google Scholar]
  17. Li B., Rossman M. D., Imir T., Oner-Eyuboglu A. F., Lee C. W., Biancaniello R., Carding S. R. Disease-specific changes in gammadelta T cell repertoire and function in patients with pulmonary tuberculosis. J Immunol. 1996 Nov 1;157(9):4222–4229. [PubMed] [Google Scholar]
  18. Mackaness G. B. The influence of immunologically committed lymphoid cells on macrophage activity in vivo. J Exp Med. 1969 May 1;129(5):973–992. doi: 10.1084/jem.129.5.973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Nick S., Pileri P., Tongiani S., Uematsu Y., Kappos L., De Libero G. T cell receptor gamma delta repertoire is skewed in cerebrospinal fluid of multiple sclerosis patients: molecular and functional analyses of antigen-reactive gamma delta clones. Eur J Immunol. 1995 Feb;25(2):355–363. doi: 10.1002/eji.1830250208. [DOI] [PubMed] [Google Scholar]
  20. North R. J. T cell dependence of macrophage activation and mobilization during infection with Mycobacterium tuberculosis. Infect Immun. 1974 Jul;10(1):66–71. doi: 10.1128/iai.10.1.66-71.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Panchamoorthy G., McLean J., Modlin R. L., Morita C. T., Ishikawa S., Brenner M. B., Band H. A predominance of the T cell receptor V gamma 2/V delta 2 subset in human mycobacteria-responsive T cells suggests germline gene encoded recognition. J Immunol. 1991 Nov 15;147(10):3360–3369. [PubMed] [Google Scholar]
  22. Pancholi P., Mirza A., Bhardwaj N., Steinman R. M. Sequestration from immune CD4+ T cells of mycobacteria growing in human macrophages. Science. 1993 May 14;260(5110):984–986. doi: 10.1126/science.8098550. [DOI] [PubMed] [Google Scholar]
  23. Pannetier C., Cochet M., Darche S., Casrouge A., Zöller M., Kourilsky P. The sizes of the CDR3 hypervariable regions of the murine T-cell receptor beta chains vary as a function of the recombined germ-line segments. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4319–4323. doi: 10.1073/pnas.90.9.4319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Pechhold K., Wesch D., Schondelmaier S., Kabelitz D. Primary activation of V gamma 9-expressing gamma delta T cells by Mycobacterium tuberculosis. Requirement for Th1-type CD4 T cell help and inhibition by IL-10. J Immunol. 1994 May 15;152(10):4984–4992. [PubMed] [Google Scholar]
  25. Pfeffer K., Schoel B., Gulle H., Kaufmann S. H., Wagner H. Primary responses of human T cells to mycobacteria: a frequent set of gamma/delta T cells are stimulated by protease-resistant ligands. Eur J Immunol. 1990 May;20(5):1175–1179. doi: 10.1002/eji.1830200534. [DOI] [PubMed] [Google Scholar]
  26. Poccia F., Boullier S., Lecoeur H., Cochet M., Poquet Y., Colizzi V., Fournie J. J., Gougeon M. L. Peripheral V gamma 9/V delta 2 T cell deletion and anergy to nonpeptidic mycobacterial antigens in asymptomatic HIV-1-infected persons. J Immunol. 1996 Jul 1;157(1):449–461. [PubMed] [Google Scholar]
  27. Poquet Y., Constant P., Peyrat M. A., Poupot R., Halary F., Bonneville M., Fournié J. J. High-pH anion-exchange chromatographic analysis of phosphorylated compounds: application to isolation and characterization of nonpeptide mycobacterial antigens. Anal Biochem. 1996 Dec 1;243(1):119–126. doi: 10.1006/abio.1996.0489. [DOI] [PubMed] [Google Scholar]
  28. Schoel B., Sprenger S., Kaufmann S. H. Phosphate is essential for stimulation of V gamma 9V delta 2 T lymphocytes by mycobacterial low molecular weight ligand. Eur J Immunol. 1994 Aug;24(8):1886–1892. doi: 10.1002/eji.1830240826. [DOI] [PubMed] [Google Scholar]
  29. Tanaka Y., Sano S., Nieves E., De Libero G., Rosa D., Modlin R. L., Brenner M. B., Bloom B. R., Morita C. T. Nonpeptide ligands for human gamma delta T cells. Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8175–8179. doi: 10.1073/pnas.91.17.8175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Tazi A., Bouchonnet F., Valeyre D., Cadranel J., Battesti J. P., Hance A. J. Characterization of gamma/delta T-lymphocytes in the peripheral blood of patients with active tuberculosis. A comparison with normal subjects and patients with sarcoidosis. Am Rev Respir Dis. 1992 Nov;146(5 Pt 1):1216–1221. doi: 10.1164/ajrccm/146.5_Pt_1.1216. [DOI] [PubMed] [Google Scholar]
  31. Tazi A., Fajac I., Soler P., Valeyre D., Battesti J. P., Hance A. J. Gamma/delta T-lymphocytes are not increased in number in granulomatous lesions of patients with tuberculosis or sarcoidosis. Am Rev Respir Dis. 1991 Dec;144(6):1373–1375. doi: 10.1164/ajrccm/144.6.1373. [DOI] [PubMed] [Google Scholar]
  32. Ueta C., Kawasumi H., Fujiwara H., Miyagawa T., Kida H., Ohmoto Y., Kishimoto S., Tsuyuguchi I. Interleukin-12 activates human gamma delta T cells: synergistic effect of tumor necrosis factor-alpha. Eur J Immunol. 1996 Dec;26(12):3066–3073. doi: 10.1002/eji.1830261237. [DOI] [PubMed] [Google Scholar]
  33. Ueta C., Tsuyuguchi I., Kawasumi H., Takashima T., Toba H., Kishimoto S. Increase of gamma/delta T cells in hospital workers who are in close contact with tuberculosis patients. Infect Immun. 1994 Dec;62(12):5434–5441. doi: 10.1128/iai.62.12.5434-5441.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wesch D., Kabelitz D., Friese K., Pechhold K. Mycobacteria-reactive gamma delta T cells in HIV-infected individuals: lack of V gamma 9 cell responsiveness is due to deficiency of antigen-specific CD4 T helper type 1 cells. Eur J Immunol. 1996 Mar;26(3):557–562. doi: 10.1002/eji.1830260309. [DOI] [PubMed] [Google Scholar]
  35. Wilkinson R. J., Vordermeier H. M., Wilkinson K. A., Sjölund A., Moreno C., Pasvol G., Ivanyi J. Peptide-specific T cell response to Mycobacterium tuberculosis: clinical spectrum, compartmentalization, and effect of chemotherapy. J Infect Dis. 1998 Sep;178(3):760–768. doi: 10.1086/515336. [DOI] [PubMed] [Google Scholar]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ

RESOURCES