Recognition of conserved antigens by Th17 cells provides broad protection against pulmonary Haemophilus influenzae infection
Recognition of conserved antigens by Th17 cells provides broad protection against pulmonary Haemophilus influenzae infection
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DOI：
10.1073/pnas.1802261115
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发表时间：
2018-07-24
影响因子：
11.1
通讯作者：
Shen, Hao
中科院分区：
文献类型：
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作者：
Li, Wenchao;Zhang, Xinyun;Shen, Hao
不可分型流感嗜血杆菌（NTHi）是社区获得性肺炎和慢性阻塞性肺疾病恶化的主要原因。目前在NTHi疫苗开发方面的努力主要集中在产生体液反应，并受到众多循环NTHi菌株之间抗原变异的极大阻碍。在这项研究中，我们发现杀死NTHi的小鼠肺部免疫对不同菌株的肺部感染产生广泛的保护作用。虽然免疫抗体的被动转移只对同源菌株起保护作用，但免疫T细胞的转移对同源和异源菌株都具有保护作用。进一步的表征表明Th17对不同的NTHi菌株有很强的交叉反应。应答的Th17细胞识别胞质和膜相关抗原，而免疫抗体优先应答表面抗原，具有高度的菌株特异性。我们进一步鉴定了NTHi感染期间肺Th17细胞识别的几个保守蛋白。用纯化蛋白加佐剂免疫小鼠，测试了两种产生最强反应的蛋白作为候选疫苗。免疫诱导抗原特异性Th17细胞识别不同的菌株，并在过继转移后给予保护。此外，免疫小鼠不仅可以抵抗NTHi菌株的攻击，还可以抵抗完全毒力的包封菌株的攻击。总之，这些结果表明，抗肺炎交叉保护的免疫机制涉及Th17细胞，它对广泛的抗原作出反应，包括那些在NTHi菌株中高度保守的抗原。这些机制见解表明，在亚单位疫苗中包含Th17抗原具有诱导广泛保护的优势，并补充了目前基于抗体的方法。
Nontypeable Haemophilus influenzae (NTHi) is a major cause of community acquired pneumonia and exacerbation of chronic obstructive pulmonary disease. A current effort in NTHi vaccine development has focused on generating humoral responses and has been greatly impeded by antigenic variation among the numerous circulating NTHi strains. In this study, we showed that pulmonary immunization of mice with killed NTHi generated broad protection against lung infection by different strains. While passive transfer of immune antibodies protected only against the homologous strain, transfer of immune T cells conferred protection against both homologous and heterologous strains. Further characterization revealed a strong Th17 response that was cross-reactive with different NTHi strains. Responding Th17 cells recognized both cytosolic and membrane-associated antigens, while immune antibodies preferentially responded to surface antigens and were highly strain specific. We further identified several conserved proteins recognized by lung Th17 cells during NTHi infection. Two proteins yielding the strongest responses were tested as vaccine candidates by immunization of mice with purified proteins plus an adjuvant. Immunization induced antigen-specific Th17 cells that recognized different strains and, upon adoptive transfer, conferred protection. Furthermore, immunized mice were protected against challenge with not only NTHi strains but also a fully virulent, encapsulated strain. Together, these results show that the immune mechanism of cross-protection against pneumonia involves Th17 cells, which respond to a broad spectrum of antigens, including those that are highly conserved among NTHi strains. These mechanistic insights suggest that inclusion of Th17 antigens in subunit vaccines offers the advantage of inducing broad protection and complements the current antibody-based approaches.