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ESAT-6 Inhibits Production of IFN- by Mycobacterium tuberculosis-Responsive Human T Cells¹

Xisheng Wang^*,, Peter F. Barnes^*,,, Karen M. Dobos-Elder, James C. Townsend^*,, Yoon-tae Chung^*,, Homayoun Shams^*,, Stephen E. Weis^¶ and Buka Samten^2,*,

^* Center for Pulmonary and Infectious Disease Control, Department of Microbiology and Immunology, and Department of Medicine, University of Texas Health Science Center, Tyler, TX 75708; Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Patholoy, Colorado State University, Ft. Collins, CO, 80523; and ^¶ Department of Internal Medicine, University of North Texas Health Sciences Center, Fort Worth, TX 76107

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- and proliferate in response to TCR activation. Recombinant ESAT-6, but not CFP10, markedly inhibited IFN- 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- but not IL-2. Preincubation of ESAT-6 with CFP10 under conditions that favor dimer formation did not affect inhibition of IFN-. ESAT-6 decreased IFN- transcription and reduced expression of the transcription factors, ATF-2 and c-Jun, which normally bind to the IFN- proximal promoter and stimulate mRNA expression. ESAT-6 inhibited T cell IFN- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (A1063514), the James Byers Cain Research Endowment, and the Center for Pulmonary and Infectious Disease Control. P.F.B. holds the Margaret E. Byers Cain Chair for Tuberculosis Research.

² Address correspondence and reprint requests to Buka Samten, CPIDC, University of Texas Health Science Center, 11937 US Highway 271, Tyler, TX 75708. E-mail address: buka.samten{at}uthct.edu

³ Abbreviations used in this paper: ESAT-6, early secreted Ag of 6 kDa; ATF, activating transcription factor; BCG, bacillus Calmette-Guérin; CFP10, culture filtrate protein of 10 kDa; CREB, cyclic AMP response element binding protein; RD, region of difference.