ESAT-6 inhibits production of IFN-gamma by Mycobacterium tuberculosis-responsive human T cells.
ESAT-6 inhibits production of IFN-gamma by Mycobacterium tuberculosis-responsive human T cells.
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DOI：
10.4049/jimmunol.0803579
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发表时间：
2009-03-15
期刊：
影响因子：
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通讯作者：
Samten B
中科院分区：
文献类型：
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作者：
Wang X;Barnes PF;Dobos-Elder KM;Townsend JC;Chung YT;Shams H;Weis SE;Samten B
结核分枝杆菌早期分泌的6kda银（ESAT-6）是一种对人T细胞有效的银，是一种假定的候选疫苗。然而，在动物模型中，ESAT-6也有助于增强毒力，介导细胞溶解，并抑制单核吞噬细胞产生IL-12。我们评估了ESAT-6及其分子伴侣，10 kDa的培养滤液蛋白（CFP10）对人T细胞产生IFN-γ和TCR激活后增殖能力的影响。重组ESAT-6，而非CFP10，以剂量依赖的方式显著抑制结核分枝杆菌或抗cd3和抗cd28联合刺激的T细胞产生IFN-γ。ESAT-6还能抑制T细胞产生IL-17和TNF-α，但不能抑制IL-2。在有利于二聚体形成的条件下，ESAT-6与CFP10预孵育不影响IFN-γ的抑制。ESAT-6降低IFN-γ转录，并降低转录因子ATF-2和c-Jun的表达，这些转录因子通常与IFN-γ近端启动子结合并刺激mRNA表达。ESAT-6通过不涉及细胞毒性或细胞凋亡的机制抑制T细胞IFN-γ分泌。ESAT-6与T细胞结合，抑制早期激活标记物的表达，但不降低ZAP70的激活。我们得出结论，ESAT-6通过影响ZAP70下游的TCR信号通路直接抑制人T细胞对分枝杆菌Ags的反应。
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.