The lung is the primary site of infection with the major human pathogen, Mycobacterium tuberculosis. Effective vaccines against M. tuberculosis must stimulate memory T cells to provide early protection in the lung. Recently, tissue-resident memory T cells (T_RM) were found to be phenotypically and transcriptional distinct from circulating memory T cells. Here, we identified M. tuberculosis-specific CD4⁺ T cells induced by recombinant influenza A viruses (rIAV) vaccines expressing M. tuberculosis peptides that persisted in the lung parenchyma with the phenotypic and transcriptional characteristics of T_RMs. To determine if these rIAV-induced CD4⁺ T_RM were protective independent of circulating memory T cells, mice previously immunized with the rIAV vaccine were treated with the sphingosine-1-phosphate receptor modulator, FTY720, prior to and during the first 17 days of M. tuberculosis challenge. This markedly reduced circulating T cells, but had no effect on the frequency of M. tuberculosis-specific CD4⁺ T_RMs in the lung parenchyma or their cytokine response to infection. Importantly, mice immunized with the rIAV vaccine were protected against M. tuberculosis infection even when circulating T cells were profoundly depleted by the treatment. Therefore, pulmonary immunization with the rIAV vaccine stimulates lung-resident CD4⁺ memory T cells that are associated with early protection against tuberculosis infection.

中文翻译：

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用重组甲型流感病毒疫苗进行肺部免疫可诱导肺部驻留的 CD4+ 记忆 T 细胞，这些细胞与预防结核病有关。

肺是人类主要病原体结核分枝杆菌感染的主要部位。针对结核分枝杆菌的有效疫苗必须刺激记忆 T 细胞以在肺部提供早期保护。最近，发现组织驻留记忆 T 细胞 ( _TRM ) 在表型和转录方面与循环记忆 T 细胞不同。在这里，我们鉴定了由表达结核分枝杆菌肽的重组甲型流感病毒 (rIAV) 疫苗诱导的结核分枝杆菌特异性 CD4 ^{+ T 细胞，这些肽持续存在于肺实质中，具有 T} _RM的表型和转录特征。确定这些 rIAV 诱导的 CD4 ⁺ T _RM独立于循环记忆 T 细胞的保护性，先前用 rIAV 疫苗免疫的小鼠在结核分枝杆菌攻击之前和期间的前 17 天用鞘氨醇-1-磷酸受体调节剂 FTY720 治疗。这显着减少了循环 T 细胞，但对肺实质中结核分枝杆菌特异性 CD4 ⁺ T _RM的频率或其细胞因子对感染的反应没有影响。重要的是，即使循环 T 细胞因治疗而严重耗尽，接种 rIAV 疫苗的小鼠也能免受结核分枝杆菌感染。因此，使用 rIAV 疫苗进行肺部免疫会刺激驻留在肺部的 CD4 ⁺与结核病感染的早期保护相关的记忆 T 细胞。