Division of Infectious Diseases, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Eur J Immunol. 2012 Feb;42(2):364-73. doi: 10.1002/eji.201141569. Epub 2011 Dec 20.
The generation of effective type 1 T helper (Th1)-cell responses is required for immunity against intracellular bacteria. However, some intracellular bacteria require interleukin (IL)-17 to drive Th1-cell immunity and subsequent protective host immunity. Here, in a model of Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccination in mice, we demonstrate that the dependence on IL-17 to drive Th1-cell responses is a host mechanism to overcome bacteria-induced IL-10 inhibitory effects. We show that BCG-induced prostaglandin-E2 (PGE2) promotes the production of IL-10 which limits Th1-cell responses, while simultaneously inducing IL-23 and Th17-cell differentiation. The ability of IL-17 to downregulate IL-10 and induce IL-12 production allows the generation of subsequent Th1-cell responses. Accordingly, BCG-induced Th17-cell responses precede the generation of Th1-cell responses in vivo, whereas the absence of the IL-23 pathway decreases BCG vaccine-induced Th17 and Th1-cell immunity and subsequent vaccine-induced protection upon M. tuberculosis challenge. Importantly, in the absence of IL-10, BCG-induced Th1-cell responses occur in an IL-17-independent manner. These novel data demonstrate a role for the IL-23/IL-17 pathway in driving Th1-cell responses, specifically to overcome IL-10-mediated inhibition and, furthermore, show that in the absence of IL-10, the generation of BCG-induced Th1-cell immunity is IL-17 independent.
产生有效的 1 型辅助性 T 细胞（Th1）反应是抵抗细胞内细菌所必需的。然而，一些细胞内细菌需要白细胞介素（IL）-17 来驱动 Th1 细胞免疫和随后的保护性宿主免疫。在这里，在小鼠牛分枝杆菌卡介苗（BCG）疫苗接种模型中，我们证明了依赖 IL-17 来驱动 Th1 细胞反应是宿主克服细菌诱导的 IL-10 抑制作用的机制。我们表明，BCG 诱导的前列腺素 E2（PGE2）促进了 IL-10 的产生，从而限制了 Th1 细胞反应，同时诱导了 IL-23 和 Th17 细胞分化。IL-17 下调 IL-10 和诱导 IL-12 产生的能力允许随后产生 Th1 细胞反应。因此，BCG 诱导的 Th17 细胞反应先于体内 Th1 细胞反应的产生，而 IL-23 途径的缺失会降低 BCG 疫苗诱导的 Th17 和 Th1 细胞免疫以及随后结核分枝杆菌挑战时疫苗诱导的保护。重要的是，在缺乏 IL-10 的情况下，BCG 诱导的 Th1 细胞反应以 IL-17 非依赖性方式发生。这些新数据表明 IL-23/IL-17 途径在驱动 Th1 细胞反应中的作用，特别是克服 IL-10 介导的抑制作用，此外，还表明在缺乏 IL-10 的情况下，BCG 诱导的 Th1 细胞免疫的产生是 IL-17 非依赖性的。
