期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-09212-y
关键词
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资金
- National Natural Sciences Foundation of China [31621061, 81530067, 31700786]
- National Basic Research Program of China [2015CB554300, 2015CB554303]
- CAS [QYZDJ-SSW-SMC026, 153831KYSB20160038, XDB2903000]
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/O-Tg 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-gamma 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.
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