Nasal vaccination stimulates CD8(+) T cells for potent protection against mucosal Brucella melitensis challenge.
Nasal vaccination stimulates CD8(+) T cells for potent protection against mucosal Brucella melitensis challenge.
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DOI：
10.1038/icb.2016.5
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发表时间：
2016-05
影响因子：
4
通讯作者：
Pascual DW
中科院分区：
文献类型：
--
作者：
Clapp B;Yang X;Thornburg T;Walters N;Pascual DW
布鲁氏菌病仍然是全世界重大的人畜共患威胁。人类和动物在口腔或气溶胶暴露后通过口咽和上呼吸道获得感染。粘膜感染后，布鲁氏菌病发展为全身性疾病。粘膜疫苗接种可以为预防疾病的传统注射方法提供可行的替代方案。使用鼻腔疫苗接种方法，发现 ΔznuA 羊种布鲁氏菌能够针对肺部布鲁氏菌攻击提供有效的保护，并将脾脏和肺部的定植减少超过 2500 倍，超过 50% 的接种小鼠没有检测到布鲁氏菌。此外，在脾脏和呼吸道淋巴结中诱导出的布鲁氏菌特异性、产生 IFN-γ 的 CD8+ T 细胞比 CD4+ T 细胞多十倍。对接种了 ΔznuA 羊种巴氏杆菌的小鼠的肺和脾 CD8+ T 细胞的评估表明，这些细胞表达了一种激活的效应记忆 (CD44hiCD62LloCCR7lo) T 细胞，产生升高水平的 IFN-γ、TNF-α、穿孔素和颗粒酶 B。为了评估这些增加的 CD8+ T 细胞数量的相对重要性，用有毒力的羊种巴氏杆菌攻击 CD8−/− 小鼠，并与受到类似攻击的 CD4−/− 小鼠相比，它们的器官中细菌载量显着增加。只有接种了 ΔznuA 羊种布鲁氏菌和 Rev-1 疫苗的 CD4−/− 和野生型小鼠，而不是 CD8−/− 小鼠，才完全免受布鲁氏菌攻击。对负责提供保护的细胞因子的测定表明，IFN-γ 相对重要，但 IL-17 则不然。与野生型小鼠不同，IL-17在IFN-γ−/−小鼠中被大量诱导，但IL-17不能替代IFN-γ的保护，尽管在体内IL-17中和后观察到布鲁氏菌传播增加。这些结果表明，经鼻 ΔznuA 羊种布鲁氏菌疫苗接种代表了一种通过 CD8+ T 细胞参与刺激全身和粘膜免疫保护的有吸引力的方法。
Brucellosis remains a significant zoonotic threat worldwide. Humans and animals acquire infection via their oropharynx and upper respiratory tract following oral or aerosol exposure. After mucosal infection, brucellosis develops into a systemic disease. Mucosal vaccination could offer a viable alternative to conventional injection practices to deter disease. Using a nasal vaccination approach, the ΔznuA B. melitensis was found to confer potent protection against pulmonary Brucella challenge, and reduce colonization of spleens and lungs by more than 2500-fold, with more than 50% of vaccinated mice showing no detectable brucellae. Furthermore, tenfold more brucellae-specific, IFN-γ-producing CD8+ T cells than CD4+ T cells were induced in the spleen and respiratory lymph nodes. Evaluation of pulmonary and splenic CD8+ T cells from mice vaccinated with ΔznuA B. melitensis revealed that these expressed an activated effector memory (CD44hiCD62LloCCR7lo) T cells producing elevated levels of IFN-γ, TNF-α, perforin, and granzyme B. To assess the relative importance of these increased numbers of CD8+ T cells, CD8−/− mice were challenged with virulent B. melitensis, and they showed markedly increased bacterial loads in organs in contrast to similarly challenged CD4−/− mice. Only ΔznuA B. melitensis- and Rev-1-vaccinated CD4−/− and wild-type mice, not CD8−/− mice, were completely protected against Brucella challenge. Determination of cytokines responsible for conferring protection showed the relative importance of IFN-γ, but not IL-17. Unlike wild-type mice, IL-17 was greatly induced in IFN-γ−/− mice, but IL-17 could not substitute for IFN-γ’s protection, although an increase in brucellae dissemination was observed upon in vivo IL-17 neutralization. These results show that nasal ΔznuA B. melitensis vaccination represents an attractive means to stimulate systemic and mucosal immune protection via CD8+ T cell engagement.