Background

Bacterial respiratory tract infections and exacerbations of chronic lung diseases are commonly caused by nontypeable Haemophilus influenzae (NTHi). Cell-mediated cytotoxicity might be key to controlling infection, but the responses of NTHi-specific T-cell populations are not well understood. Mucosal-associated invariant T (MAIT) cells are a recently discovered, innate-like subset of T cells with cytotoxic function, the role of which in lung immunity is unclear.

Objective

The aim of this study was to determine the mechanisms behind conventional T-cell and MAIT cell cytotoxic responses to NTHi.

Methods

Human ex vivo lung explants were infected with a clinical strain of NTHi. Monocyte-derived macrophages were also infected with NTHi in vitro and cocultured with autologous T cells. Cytotoxic responses of T-cell subsets were measured by using flow cytometry.

Results

We found significant upregulation of the cytotoxic markers CD107a and granzyme B in lung CD4⁺, CD8⁺, and MAIT cell populations. We show that MAIT cell cytotoxic responses were upregulated by a combination of both time-dependent antigen presentation and a novel mechanism through which IL-12 and IL-7 synergistically control granzyme B through upregulation of the IL-12 receptor.

Conclusions

Overall, our data provide evidence for a cytotoxic role of MAIT cells in the lung and highlight important differences in the control of adaptive and innate-like T-cell responses. Understanding these mechanisms might lead to new therapeutic opportunities to modulate the antibacterial response and improve clinical outcome.

中文翻译：

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IL-12和IL-7协同控制细菌感染的粘膜相关不变T细胞细胞毒性反应

背景

细菌性呼吸道感染和慢性肺部疾病加重通常是由无法分型的流感嗜血杆菌（NTHi）引起的。细胞介导的细胞毒性可能是控制感染的关键，但人们对NTHi特异性T细胞群体的反应尚不甚了解。粘膜相关不变T（MAIT）是最近发现的具有细胞毒性功能的T细胞先天性子集，其在肺部免疫中的作用尚不清楚。

客观的

这项研究的目的是确定背后的机制，传统的T细胞和MAIT细胞对NTHi的细胞毒性反应。

方法

人类离体肺外植体感染了NTHi临床菌株。单核细胞衍生的巨噬细胞也被NTHi体外感染，并与自体T细胞共培养。通过使用流式细胞仪测量T细胞亚群的细胞毒性反应。

结果

我们发现肺CD4 ⁺，CD8 ⁺和MAIT细胞群中的细胞毒性标记CD107a和颗粒酶B明显上调。我们显示，MAIT细胞的细胞毒性反应是由时间依赖性抗原呈递和IL-12和IL-7通过IL-12受体的上调协同控制粒酶B的新机制的结合而上调的。

结论

总体而言，我们的数据为MAIT细胞在肺中的细胞毒性作用提供了证据，并突显了适应性和先天性T细胞反应控制中的重要差异。了解这些机制可能会导致新的治疗机会，以调节抗菌反应并改善临床结局。