In:
Nature Communications, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2019-04-03)
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/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-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.
Type of Medium:
Online Resource
ISSN:
2041-1723
DOI:
10.1038/s41467-019-09212-y
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2019
detail.hit.zdb_id:
2553671-0
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