title: ESAT-6 inhibits production of IFN-gamma by Mycobacterium tuberculosis-responsive human T cells.
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.
authors.affiliation: Department of Microbiologyand Immunology, Center for Pulmonary and Infectious Disease Control, University of Texas Health Science Center, Tyler, TX 75708, USA.
authors.forename: Xisheng
authors.initials: X
authors.lastname: Wang
authors.forename: Peter F
authors.initials: PF
authors.lastname: Barnes
authors.forename: Karen M
authors.initials: KM
authors.lastname: Dobos-Elder
authors.forename: James C
authors.initials: JC
authors.lastname: Townsend
authors.forename: Yoon-tae
authors.initials: YT
authors.lastname: Chung
authors.forename: Homayoun
authors.initials: H
authors.lastname: Shams
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Weis
authors.forename: Buka
authors.initials: B
authors.lastname: Samten
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics / Q000502:physiology*; D015703:Antigens, CD / Q000096:biosynthesis / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D037181:Lectins, C-Type; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D000942:Antigens, Bacterial; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D001426:Bacterial Proteins; D007371:Interferon-gamma; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D051746:ZAP-70 Protein-Tyrosine Kinase; D000099192:CD69 Antigens; C093276:ESAT-6 protein, Mycobacterium tuberculosis; C497261:ZAP70 protein, human