Early secreted antigenic target of 6-kDa protein of Mycobacterium tuberculosis primes dendritic cells to stimulate Th17 and inhibit Th1 immune responses.
Early secreted antigenic target of 6-kDa protein of Mycobacterium tuberculosis primes dendritic cells to stimulate Th17 and inhibit Th1 immune responses.
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DOI：
10.4049/jimmunol.1200573
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发表时间：
2012-09-15
期刊：
影响因子：
--
通讯作者：
Samten B
中科院分区：
文献类型：
--
作者：
Wang X;Barnes PF;Huang F;Alvarez IB;Neuenschwander PF;Sherman DR;Samten B
结核分枝杆菌早期分泌的6 kD抗原靶点（ESAT-6）是一种T细胞抗原，是潜在的疫苗候选者，但它也是介导致病性的毒力因子。为了更好地理解ESAT-6对免疫应答的影响，我们研究了ESAT-6对人树突状细胞（DC）的影响。用GM-CSF和IL-4处理外周血单核细胞以产生未成熟的DC，其通过添加脂多糖（LPS）和CD 40配体（CD 40 L）（有或没有ESAT-6）而成熟。ESAT-6抑制LPS/CD 40 L诱导的DC共刺激分子的表达，减少DC刺激的同种异体T细胞增殖以及IL-2和IFN-γ的产生，并增强IL-17的产生。ESAT-6处理的DC也增加了M.结核特异性自体T细胞。ESAT-6通过与iDC的特异性相互作用抑制LPS/CD 40 L诱导的DC产生IL-12，并增强IL-23和IL-1β的产生，而不影响TNF-α、IL-6或IL-8的分泌。ESAT-6的作用不通过cAMP或p38丝裂原活化蛋白激酶介导。来自ESAT-6条件DC的培养基增加了用抗CD 3加抗CD 28刺激的T细胞的IL-17产生并减少了IFN-γ产生，并且ESAT-6诱导的IL-17产生通过中和IL-23和IL-1β而被阻断。ESAT-6通过抑制干扰素调节因子-1和上调IL-12 p35和IL-23 p19的转录调节因子活化转录因子-2和c-Jun，降低LPS/CD 40 L刺激的IL-12 p35转录，增强IL-23 p19转录。我们得出结论，ESAT-6增加DC产生IL-23和IL-1β，同时抑制IL-12，从而以保护性Th 1应答为代价增强Th 17。
Early secreted antigenic target of 6 kD (ESAT-6) of Mycobacterium tuberculosis is a T-cell antigen that is a potential vaccine candidate, but it is also a virulence factor that mediates pathogenicity. To better understand the effects of ESAT-6 on the immune response, we studied the effect of ESAT-6 on human dendritic cells (DCs). Peripheral blood monocytes were treated with GM-CSF and IL-4 to yield immature DCs, which were matured by addition of lipolysaccharide (LPS) and CD40 ligand (CD40L), with or without ESAT-6. ESAT-6 inhibited LPS/CD40L-induced DC expression of co-stimulatory molecules, reduced DC-stimulated allogeneic T cell proliferation and IL-2 and IFN-γ production, and enhanced IL-17 production. ESAT-6-treated DCs also increased IL-17 and reduced IFN-γ production by M. tuberculosis-specific autologous T cells. ESAT-6 inhibited LPS/CD40L-induced DC production of IL-12 and enhanced that of IL-23 and IL-1β, without affecting secretion of TNF-α, IL-6 or IL-8 through specific interaction with iDCs. The effects of ESAT-6 were not mediated through cAMP or p38 mitogen-activated protein kinase. Medium from ESAT-6-conditioned DCs increased IL-17 and reduced IFN-γ production by T cells stimulated with anti-CD3 plus anti-CD28, and ESAT-6-induced IL-17 production was blocked by neutralizing both IL-23 and IL-1β. ESAT-6 reduced LPS/CD40L-stimulated transcription of IL-12p35 and enhanced that of IL-23p19 through inhibition of interferon regulatory factor-1 and upregulation of activating transcription factor-2 and c-Jun, transcriptional regulators of IL-12p35 and IL-23p19, respectively. We conclude that ESAT-6 increases DC production of IL-23 and IL-1β, while inhibiting that of IL-12, thus enhancing Th17 at the expense of protective Th1 responses.
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影响因子：
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