Pulmonary M-tuberculosis infection delays Th1 immunity via immunoadaptor DAP12-regulated IRAK-M and IL-10 expression in antigen-presenting cells
Pulmonary M-tuberculosis infection delays Th1 immunity via immunoadaptor DAP12-regulated IRAK-M and IL-10 expression in antigen-presenting cells
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DOI：
10.1038/mi.2013.86
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发表时间：
2014-05-01
影响因子：
8
通讯作者：
Xing, Z.
中科院分区：
文献类型：
--
作者：
Jeyanathan, M.;McCormick, S.;Xing, Z.
分枝杆菌与宿主的相互作用导致肺中T辅助细胞1型（Th 1）免疫的表达延迟。然而，免疫机制仍然知之甚少。利用结核分枝杆菌（M. tb）感染时，我们发现抗原呈递细胞（APC）中的免疫适配体DAP 12（12 kDa的DNA X活化蛋白）在这一过程中起关键作用。感染APC后，IRAK-M（白细胞介素-1受体相关激酶M）表达需要DAP 12，IRAK-M又诱导白细胞介素-10（IL-10）和APC的免疫抑制表型，从而导致抑制的Th 1细胞活化。缺乏DAP 12会减少APC IL-10的产生，并增加其Th 1细胞活化能力，从而加快Th 1应答并增强保护作用。另一方面，过继转移的DAP 12-感受态APC抑制DAP 12缺陷宿主内的Th 1细胞活化，并且IL-10的阻断使DAP 12-感受态APC抑制Th 1活化的能力丧失。我们的研究确定了DAP 12/IRAK-M/IL-10是分枝杆菌病原体利用的APC中的一种新的分子途径，使感染在肺部立足。
Interaction of mycobacteria with the host leads to retarded expression of T helper cell type 1 (Th1) immunity in the lung. However, the immune mechanisms remain poorly understood. Using in vivo and in vitro models of Mycobacterium tuberculosis (M. tb) infection, we find the immunoadaptor DAP12 (DNAX-activating protein of 12 kDa) in antigen-presenting cells (APCs) to be critically involved in this process. Upon infection of APCs, DAP12 is required for IRAK-M (interleukin-1 receptor-associated kinase M) expression, which in turn induces interleukin-10 (IL-10) and an immune-suppressed phenotype of APCs, thus leading to suppressed Th1 cell activation. Lack of DAP12 reduces APC IL-10 production and increases their Th1 cell-activating capability, resulting in expedited Th1 responses and enhanced protection. On the other hand, adoptively transferred DAP12-competent APCs suppress Th1 cell activation within DAP12-deficient hosts, and blockade of IL-10 aborts the ability of DAP12-competent APCs to suppress Th1 activation. Our study identifies the DAP12/IRAK-M/IL-10 to be a novel molecular pathway in APCs exploited by mycobacterial pathogens, allowing infection a foothold in the lung.