Activation of the TLR signaling pathway in CD8 T cells counteracts liver endothelial cell-induced T cell tolerance
Activation of the TLR signaling pathway in CD8 T cells counteracts liver endothelial cell-induced T cell tolerance
复制标题
CD8 T 细胞中 TLR 信号通路的激活可抵消肝内皮细胞诱导的 T 细胞耐受
DOI：
10.1038/s41423-019-0255-8
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发表时间：
2019
影响因子：
24.1
通讯作者：
Lu Mengji
中科院分区：
文献类型：
--
作者：
Zhang Ejuan;Yan Hu;Li Qian;Dittmer Ulf;Yan Huimin;Lu Mengji
The Toll-like receptor (TLR) signaling pathway, which is composed of a group of highly conserved molecules, plays a critical role in the recognition of pathogen-associated molecular patterns (PAMPs). Innate immunity activated through the TLR signaling pathway serves as a first defense against infectious diseases. 1 However, the exact function of TLR signaling in viral infections remains to be elucidated. Previously, a number of clinical reports indicated that TLR expression and function are impaired in chronic hepatitis B virus (HBV) infection. 2 A specific question was raised regarding whether deficient TLR function may contribute to chronic HBV infection, characterized by low or absent T cell responses against HBV. 3 In our previous study published in Cellular and Molecular Immunology, Ma et al. demonstrated that deficiency in TLRs or adaptor molecules (MyD88/Trif or IRAK4) resulted in not only elevated expression of HBsAg and HBV DNA but also delayed HBV clearance in the hydrodynamic injection HBV mouse model. 4 HBV-specific T cell responses, which play a key role in HBV control and clearance, 5 were detectable but functionally impaired in IL-1R/TLR deficient mice. This study highlighted the essential role of the IL-1R/TLR signaling pathway in adaptive immunity and HBV clearance in vivo. This finding suggested that TLR deficiency may be involved in the low HBV-specific T cell responses observed during chronic HBV infection in humans.The obvious question is whether TLR signaling provides direct help for hepatic T cells to enhance their immune functions. The liver is an immune-privileged organ with potent mechanisms for tolerance induction. 6 Hepatic tolerance, though crucial for maintaining liver homeostasis, limits antiviral immune responses. Typically, liver nonparenchymal cells, including liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs), facilitate intrahepatic T cell priming usually followed by T cell tolerance and functional impairment. Our previous studies showed that TLR stimulation may render LSECs but not KCs immune-activating instead of tolerogenic, indicating that T cell tolerance could be overcome by TLRs targeting the proper responding cell types. 7, 8 Recent studies point out that some TLRs are expressed by activated CD8+ T cells and serve as costimulatory molecules. 9 For example, TLR2 signaling in CD8+ T cells results in a reduced antigen threshold, activation of the mTOR pathway and IFN-γ production. Therefore, we presume that the TLR activation of CD8+ T cells may promote their ability to maintain functionality in the liver. To address this hypothesis, murine splenocytes were prestimulated with TLR2 or TLR7 ligands (P3C or R848, respectively) and activated by anti-CD3 antibodies in the presence of naïve LSECs after washing out free TLR
