Microbial Lipid A Remodeling Controls Cross-Presentation Efficiency and CD8 T Cell Priming by Modulating Dendritic Cell Function.
Microbial Lipid A Remodeling Controls Cross-Presentation Efficiency and CD8 T Cell Priming by Modulating Dendritic Cell Function.
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微生物脂质 A 重塑通过调节树突状细胞功能来控制交叉呈递效率和 CD8 T 细胞启动。
DOI：
10.1128/iai.00335-20
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发表时间：
2021
影响因子：
3.1
通讯作者：
Genco,CarolineA
中科院分区：
文献类型：
--
作者：
Papadopoulos,George;Berland,Robert;Sunkavalli,Ashwini;Coats,StephenR;Darveau,RichardP;Genco,CarolineA
大多数革兰氏阴性细菌通过宿主免疫受体Toll样受体4（TLR4）识别细菌外膜上表达的脂质A而引发有效的免疫应答。然而，一些革兰氏阴性菌逃避TLR4的检测或通过修饰脂质A种类改变TLR4信号传导的结果。虽然脂质A修饰对宿主先天免疫的作用已被详细研究，但目前尚不清楚脂质A重塑如何影响宿主适应性免疫。改变其脂质A结构的一种原型革兰氏阴性细菌是牙龈卟啉单胞菌（Porphyromonas gingivalis），其是一种厌氧致病菌，其定殖于人类牙周组织并诱导与牙周疾病以及许多全身性炎性病症相关的慢性低度炎症。牙龈卟啉单胞菌产生去磷酸化和去酰化的脂质A结构，其在TLR4处显示改变的活性。在这里，我们探讨了牙龈卟啉单胞菌脂质A修饰对小鼠骨髓来源的树突状细胞（BMDC）中TLR4依赖性先天性和适应性免疫应答的功能作用。我们发现牙龈卟啉单胞菌需要去除脂质A4 ′-磷酸以逃避BMDC依赖性促炎细胞因子反应，并显著限制细菌诱导β干扰素（IFN-β）产生的能力。此外，脂质A 4 ′-磷酸酶活性可防止典型细菌诱导的抗原降解延迟，这导致抗原交叉呈递效率低下，无法交叉致敏对牙龈卟啉单胞菌相关抗原具有特异性的CD8 T细胞。我们认为，这种细菌产生的脂质A修饰改变宿主TLR4依赖性适应性免疫，以建立与一些全身性炎症性疾病相关的慢性感染。
The majority of Gram-negative bacteria elicit a potent immune response via recognition of lipid A expressed on the outer bacterial membrane by the host immune receptor Toll-like receptor 4 (TLR4). However, some Gram-negative bacteria evade detection by TLR4 or alter the outcome of TLR4 signaling by modification of lipid A species. Although the role of lipid A modifications on host innate immunity has been examined in some detail, it is currently unclear how lipid A remodeling influences host adaptive immunity. One prototypic Gram-negative bacterium that modifies its lipid A structure is Porphyromonas gingivalis, an anaerobic pathobiont that colonizes the human periodontium and induces chronic low-grade inflammation that is associated with periodontal disease as well as a number of systemic inflammatory disorders. P. gingivalis produces dephosphorylated and deacylated lipid A structures displaying altered activities at TLR4. Here, we explored the functional role of P. gingivalis lipid A modifications on TLR4-dependent innate and adaptive immune responses in mouse bone marrow-derived dendritic cells (BMDCs). We discovered that lipid A 4′-phosphate removal is required for P. gingivalis to evade BMDC-dependent proinflammatory cytokine responses and markedly limits the bacterium’s capacity to induce beta interferon (IFN-β) production. In addition, lipid A 4′-phosphatase activity prevents canonical bacterium-induced delay in antigen degradation, which leads to inefficient antigen cross-presentation and a failure to cross-prime CD8 T cells specific for a P. gingivalis-associated antigen. We propose that lipid A modifications produced by this bacterium alter host TLR4-dependent adaptive immunity to establish chronic infections associated with a number of systemic inflammatory disorders.