Defects in acute responses to TLR4 in Btk-deficient mice result in impaired dendritic cell-induced IFN-γ production by natural killer cells
Defects in acute responses to TLR4 in Btk-deficient mice result in impaired dendritic cell-induced IFN-γ production by natural killer cells
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DOI：
10.1016/j.clim.2011.12.009
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发表时间：
2012-03-01
影响因子：
8.6
通讯作者：
Jefferies, Caroline A.
中科院分区：
文献类型：
--
作者：
Gabhann, Joan Ni;Spence, Shaun;Jefferies, Caroline A.
这项研究确定了Btk在调节TLR 4诱导的抗原呈递细胞（APC）和自然杀伤（NK）细胞之间的串扰中的关键作用。在Btk缺陷小鼠和急性LPS施用后离体产生的巨噬细胞和树突状细胞（DC）中观察到IL-12、IL-18和IFN-γ水平降低，同时观察到IL-10产生增强。此外，在不存在Btk的情况下，APC上的活化标志物和抗原呈递分子的上调也受损。APC凭借其产生IL-12和IL-18的能力，是NK衍生的IFN-γ的强诱导剂。共培养实验表明，Btk缺陷型DC不能驱动野生型或Btk缺陷型NK细胞诱导IFN-γ产生，而这些反应可以通过外源性施用IL-12和IL-18来恢复。因此，Btk是APC诱导的NK细胞活化的关键调节剂，因为其能够响应于急性LPS施用而调节IL-12和IL-18产生。(C)2011 Elsevier Inc. All rights reserved.
This study defines a critical role for Btk in regulating TLR4-induced crosstalk between antigen presenting cells (APCs) and natural killer (NK) cells. Reduced levels of IL-12, IL-18 and IFN-gamma were observed in Btk-deficient mice and ex vivo generated macrophages and dendritic cells (DCs) following acute LPS administration, whilst enhanced IL-10 production was observed. In addition, upregulation of activation markers and antigen presentation molecules on APCs was also impaired in the absence of Btk. APCs, by virtue of their ability to produce IL-12 and IL-18, are strong inducers of NK-derived IFN-gamma. Co-culture experiments demonstrate that Btk-deficient DCs were unable to drive wild-type or Btk-deficient NK cells to induce IFN-gamma production, whereas these responses could be restored by exogenous administration of IL-12 and IL-18. Thus Btk is a critical regulator of APC-induced NK cell activation by virtue of its ability to regulate IL-12 and IL-18 production in response to acute LPS administration. (C) 2011 Elsevier Inc. All rights reserved.