T cell-mediated protection against Mycobacterium tuberculosis (Mtb) is dependent upon the ability to localize within the site of pulmonary infection and directly interact with infected cells. In turn, vaccine strategies to improve rapid T cell targeting of Mtb-infected cells after pulmonary exposure are being actively pursued. Given parenterally, the subunit vaccine H56:CAF01 elicits polyfunctional CD4 T cells that localize to the lung parenchyma and confer durable protection. Here, we find that airway mucosal boosting of parenteral H56:CAF01 immunization greatly enhances the population of long-lived lung-resident T cells (Trm) and increases early vaccine T cell responses to pulmonary Mtb challenge in multiple mouse models. However, mucosal boosting does not alter the Th1/17 vaccine signature typical of H56:CAF01 and does not further improve durable control of pulmonary infection following aerosol Mtb-challenge. Additional mucosal boosting with H56:CAF01 further enhances the Trm response without further improving protection, while blocking the recruitment of non-Trm with FTY720-treatment failed to exposed Trm-mediated protection in mucosally boosting animals. These results demonstrate the limitations of maximizing lung-localized Trm in vaccine control of pulmonary Mtb infection, especially within an immunization protocol that is already optimized for the induction of mucosal-homing Th17 cells.

T 细胞介导的抗结核分枝杆菌保护作用(Mtb) 取决于在肺部感染部位内定位并直接与感染细胞相互作用的能力。反过来，正在积极寻求提高肺部暴露后 Mtb 感染细胞的快速 T 细胞靶向的疫苗策略。肠胃外给予亚单位疫苗 H56:CAF01 可引发多功能 CD4 T 细胞，这些细胞定位于肺实质并提供持久保护。在这里，我们发现肠胃外 H56:CAF01 免疫的气道粘膜增强大大增加了长寿命肺驻留 T 细胞 (Trm) 的数量，并增加了多种小鼠模型中早期疫苗 T 细胞对肺部 Mtb 攻击的反应。然而，粘膜加强免疫不会改变 H56 典型的 Th1/17 疫苗特征：CAF01 并没有进一步改善气溶胶 Mtb 攻击后肺部感染的持久控制。用 H56:CAF01 进行的额外粘膜增强可进一步增强 Trm 反应，而不会进一步改善保护，而用 FTY720 处理阻止非 Trm 的募集未能在粘膜增强动物中暴露 Trm 介导的保护。这些结果证明了在肺部 Mtb 感染的疫苗控制中最大化肺局部 Trm 的局限性，特别是在已经针对粘膜归巢 Th17 细胞的诱导进行了优化的免疫方案中。