Division of Immunoregulation, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom.
J Immunol. 2012 Oct 15;189(8):4079-87. doi: 10.4049/jimmunol.1201061. Epub 2012 Sep 12.
Vaccination with Mycobacterium bovis bacillus Calmette-Guérin (BCG) remains the only prophylactic vaccine against tuberculosis, caused by Mycobacterium tuberculosis, but gives variable protection against pulmonary disease. The generation of host Th1 responses following BCG vaccination is accepted as the major mechanism of protection against M. tuberculosis infection. Early production of IL-17 in the lungs following M. tuberculosis challenge of mice previously vaccinated with M. tuberculosis peptides in adjuvant has been shown to be required for efficient Th1 cell recruitment. IL-10 regulates various processes involved in generation of Th1 and Th17 responses. Previous studies have shown IL-10 as a negative regulator of the immune response to primary M. tuberculosis infection, with Il10(-/-) mice having reduced lung bacterial loads. In this study we show that inhibition of IL-10 signaling during BCG vaccination enhances host-generated Ag-specific IFN-γ and IL-17A responses, and that this regimen gives significantly greater protection against aerogenic M. tuberculosis challenge in both susceptible and relatively resistant strains of mice. In M. tuberculosis-susceptible CBA/J mice, Ab blockade of IL-10R specifically during BCG vaccination resulted in additional protection against M. tuberculosis challenge of >1-log(10) compared with equivalent isotype-treated controls. The protection observed following BCG vaccination concurrent with anti-IL-10R mAb treatment was sustained through chronic M. tuberculosis infection and correlated with enhanced lung Th1 and Th17 responses and increased IFN-γ and IL-17A production by γδ T cells and an innate-like Thy1.2(+)CD3(-) lymphoid population. We show that IL-10 inhibits optimal BCG-elicited protection, therefore suggesting that antagonists of IL-10 may be of great benefit as adjuvants in preventive vaccination against tuberculosis.
牛型结核分枝杆菌（BCG）疫苗仍然是预防由结核分枝杆菌引起的结核病的唯一预防性疫苗，但对肺部疾病的保护作用各不相同。BCG 疫苗接种后宿主 Th1 反应的产生被认为是预防结核分枝杆菌感染的主要机制。先前用结核分枝杆菌肽佐剂接种的小鼠在受到结核分枝杆菌挑战后，肺部早期产生的白细胞介素-17（IL-17）已被证明是有效招募 Th1 细胞所必需的。IL-10 调节与 Th1 和 Th17 反应产生相关的各种过程。先前的研究表明，IL-10 是对原发性结核分枝杆菌感染免疫反应的负调节剂，Il10(-/-) 小鼠的肺部细菌负荷减少。在这项研究中，我们表明在 BCG 接种期间抑制 IL-10 信号会增强宿主产生的抗原特异性 IFN-γ 和 IL-17A 反应，并且这种方案在易感和相对抗性的小鼠菌株中对气溶胶性结核分枝杆菌挑战提供了显著更大的保护。在结核分枝杆菌易感的 CBA/J 小鼠中，在 BCG 接种期间特异性阻断 IL-10R 的 Ab 导致与等效的同种型处理对照相比，对结核分枝杆菌挑战的保护增加了>1 个对数（10）。在 BCG 接种期间与抗 IL-10R mAb 治疗同时观察到的保护作用通过慢性结核分枝杆菌感染得以维持，并与增强的肺部 Th1 和 Th17 反应以及由γδ T 细胞和先天样 Thy1.2(+)CD3(-)淋巴样群体产生的 IFN-γ 和 IL-17A 增加相关。我们表明，IL-10 抑制了最佳的 BCG 引发的保护作用，因此表明 IL-10 的拮抗剂可能作为预防性结核病疫苗接种的佐剂具有巨大的益处。
