Intrahepatic myeloid-cell aggregates enable local proliferation of CD8+T cells and successful immunotherapy against chronic viral liver infection
Intrahepatic myeloid-cell aggregates enable local proliferation of CD8+T cells and successful immunotherapy against chronic viral liver infection
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DOI：
10.1038/ni.2573
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发表时间：
2013-06-01
影响因子：
30.5
通讯作者：
Knolle, Percy A.
中科院分区：
文献类型：
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作者：
Huang, Li-Rung;Wohlleber, Dirk;Knolle, Percy A.
慢性感染是难以克服的，因为细胞毒性效应CD8+ T细胞（细胞毒性T淋巴细胞（ctl））的衰竭或耗竭。在这里，我们报告了通过toll样受体（TLRs）的信号传导诱导肝内骨髓细胞聚集，使ctl群体扩增（iMATEs：“肝内骨髓细胞聚集促进T细胞群体扩增”），而不引起免疫病理学。在肝脏中，CTL增殖仅限于由炎性单核细胞来源的CD11b（+）细胞组成的iMATEs。通过肿瘤坏死因子（TNF）的信号传导引起iMATE的形成，促进依赖受体OX40的共刺激，以扩大CTL群体。imate在急性病毒感染时出现，而在慢性病毒感染时不存在，但它们仍然是由TLR信号诱导的。这种肝扩增的CTL群体控制了DNA接种后肝脏的慢性病毒感染。因此，imate是一种动态结构，可以克服慢性感染期间限制ctl群体扩张的调控线索，并可用于新的治疗性疫苗接种策略。
Chronic infection is difficult to overcome because of exhaustion or depletion of cytotoxic effector CD8+ T cells (cytotoxic T lymphoytes (CTLs)). Here we report that signaling via Toll-like receptors (TLRs) induced intrahepatic aggregates of myeloid cells that enabled the population expansion of CTLs (iMATEs: 'intrahepatic myeloid-cell aggregates for T cell population expansion') without causing immunopa thology. In the liver, CTL proliferation was restricted to iMATEs that were composed of inflammatory monocyte-derived CD11b(+) cells. Signaling via tumor-necrosis factor (TNF) caused iMATE formation that facilitated costimulation dependent on the receptor OX40 for expansion of the CTL population. The iMATEs arose during acute viral infection but were absent during chronic viral infection, yet they were still induced by TLR signaling. Such hepatic expansion of the CTL population controlled chronic viral infection of the liver after vaccination with DNA. Thus, iMATEs are dynamic structures that overcome regulatory cues that limit the population expansion of CTLs during chronic infection and can be used in new therapeutic vaccination strategies.