Type IINKT cell-mediated anergy induction in type INKT cells prevents inflammatory liver disease
Type IINKT cell-mediated anergy induction in type INKT cells prevents inflammatory liver disease
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DOI：
10.1172/jci31602
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发表时间：
2007-08-01
影响因子：
15.9
通讯作者：
Kumar, Vipin
中科院分区：
文献类型：
--
作者：
Halder, Ramesh C.;Aguilera, Carlos;Kumar, Vipin
由于已知的NKT细胞自身脂质反应性配体稀少，不同NKT细胞亚群之间的相互作用以及识别自身糖脂后的免疫后果此前尚未得到研究。在此，我们研究了在识别脑硫脂（一种CD1d限制性II型NKT细胞亚群的自身糖脂配体）后的细胞相互作用以及随后的免疫调节机制。利用糖脂/CD1d四聚体和细胞因子反应，我们表明脑硫脂反应性II型NKT细胞和浆细胞样树突状细胞的激活导致I型或恒定NKT（iNKT）细胞依赖白细胞介素 - 12（IL - 12）和巨噬细胞炎性蛋白 - 2（MIP - 2）募集到小鼠肝脏中。这些被募集的iNKT细胞无反应性，并通过特异性阻断效应通路（包括注射刀豆蛋白A（ConA）后出现的细胞因子爆发和中性粒细胞募集）预防ConA诱导的肝炎。来自白细胞介素 - 12阳性（IL - 12(+)/(+)）小鼠而非白细胞介素 - 12阴性（IL - 12(-)/(-)）小鼠的肝脏树突状细胞在受体中过继转移无反应性；因此，树突状细胞分泌白细胞介素 - 12使它们能够诱导iNKT细胞无反应性。我们的数据揭示了我们认为的一种新机制，即II型NKT细胞和肝脏树突状细胞之间的相互作用导致iNKT细胞活性的调节，这可用于干预炎症性疾病，包括自身免疫性疾病和哮喘。
Because of the paucity of known self lipid-reactive ligands for NKT cells, interactions among distinct NKT cell subsets as well as immune consequences following recognition of self glycolipids have not previously been investigated. Here we examined cellular interactions and subsequent immune regulatory mechanism following recognition of sulfatide, a self-glycolipid ligand for a subset of CD1d-restricted type II NKT cells. Using glycolipid/CD1d tetramers and cytokine responses, we showed that activation of sulfatide-reactive type II NKT cells and plasmacytoid DCs caused IL-12- and MIP-2-dependent recruitment of type I, or invariant, NKT (iNKT) cells into mouse livers. These recruited iNKT cells were anergic and prevented concanavalin A-induced (ConA-induced) hepatitis by specifically blocking effector pathways, including the cytokine burst and neutrophil recruitment that follow ConA injection. Hepatic DCs from IL-12(+)/(+)mice, but not IL-12(-)/(-) mice, adoptively transferred anergy in recipients; thus, IL-12 secretion by DCs enables them to induce anergy in iNKT cells. Our data reveal what we believe to be a novel mechanism in which interactions among type II NKT cells and hepatic DCs result in regulation of iNKT cell activity that can be exploited for intervention in inflammatory diseases, including autoimmunity and asthma.