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Activation of the TLR signaling pathway in CD8+ T cells counteracts liver endothelial cell-induced T cell tolerance

Cellular & Molecular Immunology volume 16, pages 774–776 (2019)Cite this article

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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

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Acknowledgments

This work was supported by grants from Deutsche Forschungsgemeinschaft (TRR60 and GK1949) and the National Science Foundation of China (No. 81771688 and 81461130019). We thank Juan Min and Ding Gao in the core facility for technical support of the Wuhan Institute of Virology for their kind help in flow cytometry and CyTOF analysis, respectively.

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Authors and Affiliations

  1. Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China

    Ejuan Zhang, Hu Yan & Huimin Yan

  2. Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany

    Qian Li, Ulf Dittmer & Mengji Lu

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  1. Ejuan Zhang
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Correspondence to Mengji Lu.

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Zhang, E., Yan, H., Li, Q. et al. Activation of the TLR signaling pathway in CD8+ T cells counteracts liver endothelial cell-induced T cell tolerance. Cell Mol Immunol 16, 774–776 (2019). https://doi.org/10.1038/s41423-019-0255-8

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