TLR3 signaling in macrophages is indispensable for the protective immunity of invariant natural killer T cells against enterovirus 71 infection.
TLR3 signaling in macrophages is indispensable for the protective immunity of invariant natural killer T cells against enterovirus 71 infection.
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巨噬细胞中的 TLR3 信号传导对于恒定自然杀伤 T 细胞针对肠道病毒 71 感染的保护性免疫至关重要。
DOI：
10.1371/journal.ppat.1004613
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发表时间：
2015-01
期刊：
影响因子：
6.7
通讯作者：
Leng Q
中科院分区：
文献类型：
--
作者：
Zhu K;Yang J;Luo K;Yang C;Zhang N;Xu R;Chen J;Jin M;Xu B;Guo N;Wang J;Chen Z;Cui Y;Zhao H;Wang Y;Deng C;Bai L;Ge B;Qin CF;Shen H;Yang CF;Leng Q
肠道病毒71（EV 71）是肠道病毒中致病力最强的病原体，可引起儿童手足口病，但很少引起成人手足口病。决定年龄依赖性易感性的机制在很大程度上仍不清楚。在这里，我们发现，缺乏不变的自然杀伤T（iNKT）细胞以及免疫系统的不成熟与新生小鼠对EV 71感染的易感性有关。iNKT细胞是关键的抗病毒效应细胞，以保护年轻小鼠在其适应性免疫系统完全成熟之前免受EV 71感染。EV 71感染导致iNKT细胞的活化，这取决于通过TLR 3而不是其他TLRs的信号传导。令人惊讶的是，EV 71感染期间的iNKT细胞活化需要巨噬细胞中的TLR 3信号传导，但不需要树突状细胞（DC）中的TLR 3信号传导。从机制上讲，白细胞介素（IL）-12和内源性CD 1d限制性抗原都是iNKT细胞完全激活所必需的。此外，CD 1d缺陷导致中枢神经系统病毒载量显着增加，并导致EV 71感染小鼠的疾病更加严重。总而言之，我们的研究结果表明，当儿童的适应性免疫系统尚未完全发育时，iNKT细胞可能参与控制EV 71感染，并且还意味着iNKT细胞可能是治疗EV 71感染患者的干预靶点。肠道病毒71型（EV 71）是引起手足口病的主要病原体。EV 71感染主要发生在儿童，但很少发生在成人。决定儿童对EV 71感染易感性的因素仍然难以捉摸。在这里，我们发现新生小鼠中缺乏不变的自然杀伤T（iNKT）细胞与它们对EV 71感染的易感性有关。此外，在适应性免疫系统完全发育之前，iNKT细胞在保护年长的年轻小鼠免受EV 71感染方面发挥了关键作用。从机制上讲，巨噬细胞中的TLR 3信号传导，而不是树突状细胞中的TLR 3信号传导，是EV 71感染期间iNKT细胞活化所必需的。白细胞介素（IL）-12的生产和内源性脂质抗原提出的巨噬细胞所需的完全iNKT细胞活化。iNKT细胞有阻止EV 71向中枢神经系统传播的趋势。综上所述，我们的研究结果为儿童对EV 71感染的易感性提供了新的见解，并意味着操纵iNKT细胞可能代表手足口病和儿童其他病毒感染性疾病的潜在治疗策略。
Enterovirus 71 (EV71) is the most virulent pathogen among enteroviruses that cause hand, foot and mouth disease in children but rarely in adults. The mechanisms that determine the age-dependent susceptibility remain largely unclear. Here, we found that the paucity of invariant natural killer T (iNKT) cells together with immaturity of the immune system was related to the susceptibility of neonatal mice to EV71 infection. iNKT cells were crucial antiviral effector cells to protect young mice from EV71 infection before their adaptive immune systems were fully mature. EV71 infection led to activation of iNKT cells depending on signaling through TLR3 but not other TLRs. Surprisingly, iNKT cell activation during EV71 infection required TLR3 signaling in macrophages, but not in dendritic cells (DCs). Mechanistically, interleukin (IL)-12 and endogenous CD1d-restricted antigens were both required for full activation of iNKT cells. Furthermore, CD1d-deficiency led to dramatically increased viral loads in central nervous system and more severe disease in EV71-infected mice. Altogether, our results suggest that iNKT cells may be involved in controlling EV71 infection in children when their adaptive immune systems are not fully developed, and also imply that iNKT cells might be an intervention target for treating EV71-infected patients. Enterovirus 71 (EV71) is a major causative pathogen of hand, foot and mouth disease. EV71 infection occurs mainly in children but rarely in adults. The factors that determine the susceptibility of children to EV71 infection remain elusive. Here, we found that the paucity of invariant natural killer T (iNKT) cells in new-born mice was associated with their susceptibility to EV71 infection. Furthermore, iNKT cells played a critical role in protecting older young mice from EV71 infection before their adaptive immune systems were fully developed. Mechanistically, TLR3 signaling in macrophages, but not in dendritic cells, was essentially required for iNKT cell activation during EV71 infection. Both interleukin (IL)-12 production and endogenous lipid antigens presented by macrophages were required for full iNKT cell activation. iNKT cells tended to prevent the dissemination of EV71 into central nervous system. Taken together, our findings provide a new insight into the susceptibility of children to EV71 infection, and imply that the manipulation of iNKT cells might represent a potential therapeutic strategy for HFMD and other viral infectious diseases in children.
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影响因子：
4.4
作者：
Hammond, K;Cain, W;Godfrey, D
通讯作者：
Godfrey, D
DOI：
10.1084/jem.20130417
发表时间：
2013-12-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Firth MA;Madera S;Beaulieu AM;Gasteiger G;Castillo EF;Schluns KS;Kubo M;Rothman PB;Vivier E;Sun JC
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Sun JC
影响因子：
64.8
作者：
Mattner, J;DeBord, KL;Bendelac, A
通讯作者：
Bendelac, A
不变的天然杀手T细胞识别微生物危险信号引起的脂质自抗原。
影响因子：
30.5
作者：
Brennan, Patrick J.;Tatituri, Raju V. V.;Brigl, Manfred;Kim, Edy Y.;Tuli, Amit;Sanderson, Joseph P.;Gadola, Stephan D.;Hsu, Fong-Fu;Besra, Gurdyal S.;Brenner, Michael B.
通讯作者：
Brenner, Michael B.
影响因子：
6.7
作者：
Juno JA;Keynan Y;Fowke KR
通讯作者：
Fowke KR