NKG2A is a NK cell exhaustion checkpoint for HCV persistence
Chao Zhang,
Xiao-mei Wang,
Shu-ran Li,
Trix Twelkmeyer,
Wei-hong Wang,
Sheng-yuan Zhang,
Shu-feng Wang,
Ji-zheng Chen,
Xia Jin,
Yu-zhang Wu,
Xin-wen Chen,
Sheng-dian Wang,
Jun-qi Niu,
Hai-rong Chen () and
Hong Tang ()
Additional contact information
Chao Zhang: Chinese Academy of Sciences
Xiao-mei Wang: The First Hospital of Jilin University
Shu-ran Li: Chinese Academy of Sciences
Trix Twelkmeyer: Chinese Academy of Sciences
Wei-hong Wang: Chinese Academy of Sciences
Sheng-yuan Zhang: Chinese Academy of Sciences
Shu-feng Wang: The Third Military Medical University
Ji-zheng Chen: Chinese Academy of Sciences
Xia Jin: Chinese Academy of Sciences
Yu-zhang Wu: The Third Military Medical University
Xin-wen Chen: Chinese Academy of Sciences
Sheng-dian Wang: Chinese Academy of Sciences
Jun-qi Niu: The First Hospital of Jilin University
Hai-rong Chen: Chinese Academy of Sciences
Hong Tang: Chinese Academy of Sciences
Nature Communications, 2019, vol. 10, issue 1, 1-11
Abstract:
Abstract Exhaustion of cytotoxic effector natural killer (NK) and CD8+ T cells have important functions in the establishment of persistent viral infections, but how exhaustion is induced during chronic hepatitis C virus (HCV) infection remains poorly defined. Here we show, using the humanized C/OTg mice permissive for persistent HCV infection, that NK and CD8+ T cells become sequentially exhausted shortly after their transient hepatic infiltration and activation in acute HCV infection. HCV infection upregulates Qa-1 expression in hepatocytes, which ligates NKG2A to induce NK cell exhaustion. Antibodies targeting NKG2A or Qa-1 prevents NK exhaustion and promotes NK-dependent HCV clearance. Moreover, reactivated NK cells provide sufficient IFN-γ that helps rejuvenate polyclonal HCV CD8+ T cell response and clearance of HCV. Our data thus show that NKG2A serves as a critical checkpoint for HCV-induced NK exhaustion, and that NKG2A blockade sequentially boosts interdependent NK and CD8+ T cell functions to prevent persistent HCV infection.
Date: 2019
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DOI: 10.1038/s41467-019-09212-y
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