Brucellosis remains the most common zoonotic disease globally. Currently no vaccines for humans exist, and conventional brucellosis vaccines for livestock fail to confer complete protection; hence, an improved vaccine is needed. Although Brucella infections primarily occur following a mucosal exposure, vaccines are administered parenterally. Few studies have considered mucosal vaccinations, or even targeting of tissue-resident memory T (TRM) cells. TRM cells protect against viral infections, but less is known of their role in bacterial infections, and even less for brucellosis. Oral prime, nasal boost with a newly developed Brucella abortus double mutant (znBAZ) confers nearly complete protection against pulmonary challenge with wild-type (wt) B. abortus 2308, and its protective efficacy is >2800-fold better than the RB51 vaccine. Vaccination with znBAZ potently stimulated CD8+ T cells, whereas mucosal vaccination with RB51 induced mostly CD4+ T cells. Subsequent analysis revealed these pulmonary CD44+ CD69+ CD8+ T cells to be either CD103+ or CD103- TRM cells, and these sequestered to the lung parenchyma as CXCR3lo and to the airways as CXCR3hi. Both CD8+ TRM subsets contained single-positive IFN-γ and TNF-α, as well as, polyfunctional cells. IL-17-producing CD8+ TRM cells were also induced by znBAZ vaccination, but in vivo IL-17 neutralization had no impact upon protection. In vivo depletion of CD4+ T cells had no impact upon protection in znBAZ-vaccinated mice. In contrast, CD4+ T cell depletion reduced RB51's protective efficacy in spleens and lungs by two- and three-logs, respectively. Although anti-CD8 mAb-treated znBAZ-vaccinated mice showed a significantly reduced pulmonary efficacy, this treatment failed to completely deplete the lung CD8+ T cells, leaving the CD103+ and CD103- CD8+ TRM cell ratios intact. Only znBAZ-vaccinated CD8-/- mice were fully sensitive to pulmonary challenge with virulent wt B. abortus 2308 since CD8+ TRM cells could not be induced. Collectively, these data demonstrate the key role of mucosal vaccination for the generation of CD8+ TRM cells in protecting against pulmonary challenge with virulent B. abortus.

中文翻译：

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针对居民记忆T细胞的免疫力最终达到针对布鲁氏菌感染的肺和全身保护作用。

布鲁氏菌病仍然是全球最常见的人畜共患病。目前尚无用于人类的疫苗，而用于牲畜的常规布鲁氏菌病疫苗无法提供全面的保护；因此，需要改进的疫苗。尽管布鲁氏菌感染主要是在粘膜暴露后发生的，但肠胃外注射疫苗。很少有研究考虑粘膜疫苗接种，甚至靶向组织驻留记忆T（TRM）细胞。TRM细胞可防止病毒感染，但人们对其在细菌感染中的作用知之甚少，对于布鲁氏菌病则知之甚少。用新开发的流产布鲁氏菌双突变体（znBAZ）进行的口服初次鼻腔加强治疗可对野生型（wt）流产布鲁氏菌2308几乎完全抵御肺部攻击，其保护功效比RB51疫苗高2800倍以上。znBAZ疫苗接种可有效刺激CD8 + T细胞，而RB51的粘膜疫苗接种则主要诱导CD4 + T细胞。随后的分析显示这些肺CD44 + CD69 + CD8 + T细胞为CD103 +或CD103-TRM细胞，它们分别以CXCR3lo和CXCR3hi的形式被隔离在肺实质中。CD8 + TRM的两个子集均包含单阳性IFN-γ和TNF-α，以及多功能细胞。znBAZ疫苗接种也诱导产生IL-17的CD8 + TRM细胞，但体内IL-17的中和对保护没有影响。体内耗竭的CD4 + T细胞对znBAZ疫苗接种的小鼠的保护没有影响。相反，CD4 + T细胞耗竭则使RB51在脾脏和肺部的保护功效分别降低了2个对数和3个对数。尽管用抗CD8 mAb治疗的znBAZ疫苗接种的小鼠显示出明显降低的肺部功效，但该治疗未能完全耗尽肺CD8 + T细胞，而CD103 +和CD103-CD8 + TRM细胞比例保持不变。由于不能诱导CD8 + TRM细胞，只有znBAZ疫苗接种的CD8-/-小鼠对强毒流产性流产布鲁氏菌2308的肺部攻击完全敏感。总体而言，这些数据证明了粘膜疫苗接种对于CD8 + TRM细胞的生成在预防强力流产双歧杆菌对肺部攻击中的关键作用。因为不能诱导CD8 + TRM细胞，所以流产2308。总体而言，这些数据证明了粘膜疫苗接种对于CD8 + TRM细胞的生成在预防强力流产双歧杆菌对肺部攻击中的关键作用。因为不能诱导CD8 + TRM细胞，所以流产2308。总体而言，这些数据证明了粘膜疫苗接种对于CD8 + TRM细胞的生成在预防强力流产双歧杆菌对肺部攻击中的关键作用。