PMID:19265145

Citation	Wang, X, Barnes, PF, Dobos-Elder, KM, Townsend, JC, Chung, YT, Shams, H, Weis, SE and Samten, B (2009) ESAT-6 inhibits production of IFN-gamma by Mycobacterium tuberculosis-responsive human T cells. J. Immunol. 182:3668-77
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-gamma and proliferate in response to TCR activation. Recombinant ESAT-6, but not CFP10, markedly inhibited IFN-gamma 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-alpha but not IL-2. Preincubation of ESAT-6 with CFP10 under conditions that favor dimer formation did not affect inhibition of IFN-gamma. ESAT-6 decreased IFN-gamma transcription and reduced expression of the transcription factors, ATF-2 and c-Jun, which normally bind to the IFN-gamma proximal promoter and stimulate mRNA expression. ESAT-6 inhibited T cell IFN-gamma 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.
Links	PubMed Online version:10.4049/jimmunol.0803579
Keywords	Antigens, Bacterial/genetics; Antigens, Bacterial/physiology; Antigens, CD/biosynthesis; Antigens, CD/metabolism; Antigens, Differentiation, T-Lymphocyte/biosynthesis; Antigens, Differentiation, T-Lymphocyte/metabolism; Bacterial Proteins/genetics; Bacterial Proteins/physiology; Cell Proliferation; Cells, Cultured; Humans; Interferon-gamma/antagonists & inhibitors; Interferon-gamma/biosynthesis; Interferon-gamma/secretion; Interleukin-2 Receptor alpha Subunit/antagonists & inhibitors; Interleukin-2 Receptor alpha Subunit/biosynthesis; Lectins, C-Type; Mycobacterium tuberculosis/immunology; Phosphorylation; Receptors, Antigen, T-Cell/physiology; Recombinant Proteins/pharmacology; Signal Transduction/immunology; T-Lymphocyte Subsets/immunology; T-Lymphocyte Subsets/microbiology; T-Lymphocyte Subsets/secretion; ZAP-70 Protein-Tyrosine Kinase/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MYCTU:ESXA		GO:0032689: negative regulation of interferon-gamma production	ECO:0000314:		P		Figure 4B	complete CACAO 11402
MYCTU:ESXA		GO:0050868: negative regulation of T cell activation	ECO:0000314:		P		Figure 7 shows that the protein down regulates early T cell activation markers	complete CACAO 11405
MYCTU:ESXA		GO:0044414: suppression of host defenses	ECO:0000314:		P		Figure 3, figure 4 (D-F). The protein suppresses important cytokines vital for host defenses.	complete CACAO 11407
MYCTU:ESXA		GO:0052085: negative regulation by symbiont of host T-cell mediated immune response	ECO:0000314:		P		Figure 4 (D-F)	complete CACAO 11410
MYCTE:A0A0H3LG06		GO:1902714: negative regulation of interferon-gamma secretion	ECO:0000314:		P		Figure 2	complete CACAO 11342
MYCTE:A0A0H3LG06		GO:0032700: negative regulation of interleukin-17 production	ECO:0000314:		P		Figure 4 (D)	complete CACAO 11343
MYCTE:A0A0H3LG06		GO:1904468: negative regulation of tumor necrosis factor secretion	ECO:0000314:		P		Figure 4 (E)	complete CACAO 11344
MYCTE:A0A0H3LG06		GO:0050868: negative regulation of T cell activation	ECO:0000314:		P		Figure 7	complete CACAO 11345

References

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