NKG2A is a NK cell exhaustion checkpoint for HCV persistence

• DOI: 10.1038/s41467-019-09212-y
• Publication Date: 2019-04-03T10:17:37Z
• Authors: 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; Hong Tang
• Keywords: 0301 basic medicine; Science; Q; Histocompatibility Antigens Class I; Membrane Proteins; Hepacivirus; CD8-Positive T-Lymphocytes; Hepatitis C, Chronic; Lymphocyte Activation; Article; 3. Good health; Killer Cells, Natural; Disease Models, Animal; Interferon-gamma; Mice; Random Allocation; 03 medical and health sciences; Hepatocytes; Animals; Cytokines; NK Cell Lectin-Like Receptor Subfamily C

AbstractExhaustion 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.