ESAT-6 inhibits production of IFN-γ by Mycobacterium tuberculosis-responsive human T cells

Xisheng Wang, Peter F. Barnes, Karen M. Dobos-Elder, James C. Townsend, Yoon Tae Chung, Homayoun Shams, Stephen Weis, Buka Samten

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Abstract

The Mycobacterium tuberculosis early secreted Ag of 6 kDa (ESAT-6) is a potent Ag for human T cells and is a putative vaccine candidate. However, ESAT-6 also contributes to virulence in animal models, mediates cellular cytolysis, and inhibits IL-12 production by mononuclear phagocytes. We evaluated the effects of ESAT-6 and its molecular chaperone, culture filtrate protein of 10 kDa (CFP10), on the capacity of human T cells to produce IFN-γ and proliferate in response to TCR activation. Recombinant ESAT-6, but not CFP10, markedly inhibited IFN-γ production by T cells stimulated with M. tuberculosis or with the combination of anti-CD3 and anti-CD28, in a dose-dependent manner. ESAT-6 also inhibited T cell production of IL-17 and TNF-α but not IL-2. Preincubation of ESAT-6 with CFP10 under conditions that favor dimer formation did not affect inhibition of IFN-γ. ESAT-6 decreased IFN-γ transcription and reduced expression of the transcription factors, ATF-2 and c-Jun, which normally bind to the IFN-γ proximal promoter and stimulate mRNA expression. ESAT-6 inhibited T cell IFN-γ secretion through mechanisms that did not involve cellular cytotoxicity or apoptosis. ESAT-6, but not CFP10, bound to T cells and inhibited expression of early activation markers without reducing activation of ZAP70. We conclude that ESAT-6 directly inhibits human T cell responses to mycobacterial Ags by affecting TCR signaling pathways downstream of ZAP70.

Original languageEnglish
Pages (from-to)3668-3677
Number of pages10
JournalJournal of Immunology
Volume182
Issue number6
DOIs
StatePublished - 15 Mar 2009

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Mycobacterium tuberculosis
T-Lymphocytes
Proteins
Activating Transcription Factors
Molecular Chaperones
Interleukin-17
Interleukin-12
Phagocytes
Interleukin-2
Virulence
Vaccines
Animal Models
Apoptosis
Messenger RNA

Cite this

Wang, X., Barnes, P. F., Dobos-Elder, K. M., Townsend, J. C., Chung, Y. T., Shams, H., ... Samten, B. (2009). ESAT-6 inhibits production of IFN-γ by Mycobacterium tuberculosis-responsive human T cells. Journal of Immunology, 182(6), 3668-3677. https://doi.org/10.4049/jimmunol.0803579
Wang, Xisheng ; Barnes, Peter F. ; Dobos-Elder, Karen M. ; Townsend, James C. ; Chung, Yoon Tae ; Shams, Homayoun ; Weis, Stephen ; Samten, Buka. / ESAT-6 inhibits production of IFN-γ by Mycobacterium tuberculosis-responsive human T cells. In: Journal of Immunology. 2009 ; Vol. 182, No. 6. pp. 3668-3677.
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abstract = "The Mycobacterium tuberculosis early secreted Ag of 6 kDa (ESAT-6) is a potent Ag for human T cells and is a putative vaccine candidate. However, ESAT-6 also contributes to virulence in animal models, mediates cellular cytolysis, and inhibits IL-12 production by mononuclear phagocytes. We evaluated the effects of ESAT-6 and its molecular chaperone, culture filtrate protein of 10 kDa (CFP10), on the capacity of human T cells to produce IFN-γ and proliferate in response to TCR activation. Recombinant ESAT-6, but not CFP10, markedly inhibited IFN-γ production by T cells stimulated with M. tuberculosis or with the combination of anti-CD3 and anti-CD28, in a dose-dependent manner. ESAT-6 also inhibited T cell production of IL-17 and TNF-α but not IL-2. Preincubation of ESAT-6 with CFP10 under conditions that favor dimer formation did not affect inhibition of IFN-γ. ESAT-6 decreased IFN-γ transcription and reduced expression of the transcription factors, ATF-2 and c-Jun, which normally bind to the IFN-γ proximal promoter and stimulate mRNA expression. ESAT-6 inhibited T cell IFN-γ secretion through mechanisms that did not involve cellular cytotoxicity or apoptosis. ESAT-6, but not CFP10, bound to T cells and inhibited expression of early activation markers without reducing activation of ZAP70. We conclude that ESAT-6 directly inhibits human T cell responses to mycobacterial Ags by affecting TCR signaling pathways downstream of ZAP70.",
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Wang, X, Barnes, PF, Dobos-Elder, KM, Townsend, JC, Chung, YT, Shams, H, Weis, S & Samten, B 2009, 'ESAT-6 inhibits production of IFN-γ by Mycobacterium tuberculosis-responsive human T cells', Journal of Immunology, vol. 182, no. 6, pp. 3668-3677. https://doi.org/10.4049/jimmunol.0803579

ESAT-6 inhibits production of IFN-γ by Mycobacterium tuberculosis-responsive human T cells. / Wang, Xisheng; Barnes, Peter F.; Dobos-Elder, Karen M.; Townsend, James C.; Chung, Yoon Tae; Shams, Homayoun; Weis, Stephen; Samten, Buka.

In: Journal of Immunology, Vol. 182, No. 6, 15.03.2009, p. 3668-3677.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Wang, Xisheng

AU - Barnes, Peter F.

AU - Dobos-Elder, Karen M.

AU - Townsend, James C.

AU - Chung, Yoon Tae

AU - Shams, Homayoun

AU - Weis, Stephen

AU - Samten, Buka

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N2 - The Mycobacterium tuberculosis early secreted Ag of 6 kDa (ESAT-6) is a potent Ag for human T cells and is a putative vaccine candidate. However, ESAT-6 also contributes to virulence in animal models, mediates cellular cytolysis, and inhibits IL-12 production by mononuclear phagocytes. We evaluated the effects of ESAT-6 and its molecular chaperone, culture filtrate protein of 10 kDa (CFP10), on the capacity of human T cells to produce IFN-γ and proliferate in response to TCR activation. Recombinant ESAT-6, but not CFP10, markedly inhibited IFN-γ production by T cells stimulated with M. tuberculosis or with the combination of anti-CD3 and anti-CD28, in a dose-dependent manner. ESAT-6 also inhibited T cell production of IL-17 and TNF-α but not IL-2. Preincubation of ESAT-6 with CFP10 under conditions that favor dimer formation did not affect inhibition of IFN-γ. ESAT-6 decreased IFN-γ transcription and reduced expression of the transcription factors, ATF-2 and c-Jun, which normally bind to the IFN-γ proximal promoter and stimulate mRNA expression. ESAT-6 inhibited T cell IFN-γ secretion through mechanisms that did not involve cellular cytotoxicity or apoptosis. ESAT-6, but not CFP10, bound to T cells and inhibited expression of early activation markers without reducing activation of ZAP70. We conclude that ESAT-6 directly inhibits human T cell responses to mycobacterial Ags by affecting TCR signaling pathways downstream of ZAP70.

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Wang X, Barnes PF, Dobos-Elder KM, Townsend JC, Chung YT, Shams H et al. ESAT-6 inhibits production of IFN-γ by Mycobacterium tuberculosis-responsive human T cells. Journal of Immunology. 2009 Mar 15;182(6):3668-3677. https://doi.org/10.4049/jimmunol.0803579