Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA.
Eur J Immunol. 2014 Mar;44(3):752-62. doi: 10.1002/eji.201343784. Epub 2014 Jan 2.
The neutralization of toxins is considered essential for protection against lethal infection with Bacillus anthracis (BA), a select agent and bioterrorism threat. However, toxin-neutralizing activity alone would not be expected to provide sterile immunity. Therefore, we hypothesized that the development of an adaptive immune response against BA is required for bacterial clearance. We found that human monocyte-derived dendritic cells (hDCs) kill germinated BA bacilli, but not nongerminated BA spores. hDCs produce IL-1β, IL-6, IL-12, and IL-23, and these cytokines are differentially regulated by germination-proficient versus germination-deficient BA spores. Moreover, the IL-23 response to BA spores is regulated by IL-1R-mediated signaling. hDCs infected with germinating BA spores stimulated autologous CD4(+) T cells to secrete IL-17A and IFN-γ in a contact-dependent and antigen-specific manner. The T-cell response to BA spores was not recapitulated by hDCs infected with germination-deficient BA spores, implying that the germination of spores into replicating bacilli triggers the proinflammatory cytokine response in hDCs. Our results provide primary evidence that hDCs can generate a BA-specific Th17 response, and help elucidate the mechanisms involved. These novel findings suggest that the IL-23/Th17 axis is involved in the immune response to anthrax in humans.
中和毒素被认为是预防炭疽杆菌（BA）致死性感染的关键，BA 是一种选择性制剂和生物恐怖威胁。然而，仅靠中和毒素的活性预计不会提供无菌免疫力。因此，我们假设针对 BA 的适应性免疫反应的发展是清除细菌所必需的。我们发现，人单核细胞衍生的树突状细胞（hDC）可杀死发芽的 BA 杆菌，但不能杀死未发芽的 BA 孢子。hDC 产生 IL-1β、IL-6、IL-12 和 IL-23，这些细胞因子的产生受到发芽能力强的 BA 孢子和发芽能力弱的 BA 孢子的差异调节。此外，IL-23 对 BA 孢子的反应受到 IL-1R 介导的信号调节。感染发芽 BA 孢子的 hDC 以接触依赖性和抗原特异性方式刺激自体 CD4(+)T 细胞分泌 IL-17A 和 IFN-γ。hDC 感染发芽能力弱的 BA 孢子不能再现对 BA 孢子的 T 细胞反应，这意味着孢子发芽成复制杆菌会引发 hDC 中的促炎细胞因子反应。我们的研究结果提供了主要证据表明 hDC 可以产生针对 BA 的 Th17 反应，并有助于阐明相关机制。这些新发现表明，IL-23/Th17 轴参与了人类对炭疽的免疫反应。
