NK cell-derived IFN-γ differentially regulates innate resistance and neutrophil response in T cell-deficient hosts infected with Mycobacterium tuberculosis
NK cell-derived IFN-γ differentially regulates innate resistance and neutrophil response in T cell-deficient hosts infected with Mycobacterium tuberculosis
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DOI：
10.4049/jimmunol.177.10.7086
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发表时间：
2006-11-15
影响因子：
4.4
通讯作者：
Sher, Alan
中科院分区：
文献类型：
--
作者：
Feng, Carl G.;Kaviratne, Mallika;Sher, Alan
虽然已知分泌IFN-γ的T细胞对于控制结核分枝杆菌感染是关键的，但是由NK细胞产生的IFN-γ对宿主对病原体的抗性的贡献还不太清楚。通过使用T细胞缺陷的RAG（-/-）小鼠，我们发现M.结核病刺激NK细胞依赖性IFN-γ在幼稚脾培养物和感染动物的肺中的产生。更重要的是，NK细胞缺陷的常见细胞因子受体γ链（-/-）RAG（-/-）动物、p40（-/-）RAG（-/-）或抗IFN-γ mAb处理的RAG（-/-）小鼠显示出对M的易感性显著增加。与未经治疗的NK-足够的RAG（-/-）对照相比，结核感染。比较IL-12 p40-和p35-缺陷RAG（-/-）小鼠的研究表明，IL-12在诱导IFN-γ介导的抗分枝杆菌效应子功能中比IL-23或其他含p40的IL-12家族成员起更关键的作用。IL-12缺陷或抗IFN-γ mAb治疗的RAG（-/-）小鼠的易感性增加不仅与细菌载量升高有关，而且与肺中粒细胞富集灶的形成有关。这种组织反应与NK细胞和其他白细胞群中粒细胞趋化性趋化因子KC和MIP-2的表达增加相关。有趣的是，在这些动物中，粒细胞的消耗进一步增加了细菌负荷并加剧了肺病理学，揭示了在IFN-γ不存在的情况下中性粒细胞的代偿功能。上述观察结果表明，NK细胞衍生的IFN-γ差异调节M中T非依赖性抗性和粒细胞功能。这表明这种反应可以作为艾滋病患者或其他CD 4（+）T细胞功能受损的个体的重要屏障。
Although it is known that IFN-gamma-secreting T cells are critical for control of Mycobacterium tuberculosis infection, the contribution of IFN-gamma produced by NK cells to host resistance to the pathogen is less well understood. By using T cell-deficient RAG(-/-) mice, we showed that M. tuberculosis stimulates NK cell-dependent IFN-gamma production in naive splenic cultures and in lungs of infected animals. More importantly, common cytokine receptor gamma-chain(-/-)RAG(-/-) animals deficient in NK cells, p40(-/-)RAG(-/-), or anti-IFN-gamma mAb-treated RAG(-/-) mice displayed significantly increased susceptibility to M. tuberculosis infection compared with untreated NK-sufficient RAG(-/-) controls. Studies comparing IL-12 p40- and p35-deficient RAG(-/-) mice indicated that IL-12 plays a more critical role in the induction of IFN-gamma-mediated antimycobacterial effector functions than IL-23 or other p40-containing IL-12 family members. The increased susceptibility of IL-12-deficient or anti-IFN-gamma mAb-treated RAG(-/-) mice was associated not only with elevated bacterial loads, but also with the development of granulocyte-enriched foci in lungs. This tissue response correlated with increased expression of the granulocyte chemotactic chemokines KC and MIP-2 in NK as well as other leukocyte populations. Interestingly, depletion of granulocytes further increased bacterial burdens and exacerbated pulmonary pathology in these animals, revealing a compensatory function for neutrophils in the absence of IFN-gamma. The above observations indicate that NK cell-derived IFN-gamma differentially regulates T-independent resistance and granulocyte function in M. tuberculosis infection and suggest that this response could serve as an important barrier in AIDS patients or other individuals with compromised CD4(+) T cell function.