Cargando…
NKG2A is a NK cell exhaustion checkpoint for HCV persistence
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...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447531/ https://www.ncbi.nlm.nih.gov/pubmed/30944315 http://dx.doi.org/10.1038/s41467-019-09212-y |
_version_ | 1783408511732940800 |
---|---|
author | Zhang, Chao Wang, Xiao-mei Li, Shu-ran Twelkmeyer, Trix Wang, Wei-hong Zhang, Sheng-yuan Wang, Shu-feng Chen, Ji-zheng Jin, Xia Wu, Yu-zhang Chen, Xin-wen Wang, Sheng-dian Niu, Jun-qi Chen, Hai-rong Tang, Hong |
author_facet | Zhang, Chao Wang, Xiao-mei Li, Shu-ran Twelkmeyer, Trix Wang, Wei-hong Zhang, Sheng-yuan Wang, Shu-feng Chen, Ji-zheng Jin, Xia Wu, Yu-zhang Chen, Xin-wen Wang, Sheng-dian Niu, Jun-qi Chen, Hai-rong Tang, Hong |
author_sort | Zhang, Chao |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6447531 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-64475312019-04-05 NKG2A is a NK cell exhaustion checkpoint for HCV persistence Zhang, Chao Wang, Xiao-mei Li, Shu-ran Twelkmeyer, Trix Wang, Wei-hong Zhang, Sheng-yuan Wang, Shu-feng Chen, Ji-zheng Jin, Xia Wu, Yu-zhang Chen, Xin-wen Wang, Sheng-dian Niu, Jun-qi Chen, Hai-rong Tang, Hong Nat Commun Article 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. Nature Publishing Group UK 2019-04-03 /pmc/articles/PMC6447531/ /pubmed/30944315 http://dx.doi.org/10.1038/s41467-019-09212-y Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Zhang, Chao Wang, Xiao-mei Li, Shu-ran Twelkmeyer, Trix Wang, Wei-hong Zhang, Sheng-yuan Wang, Shu-feng Chen, Ji-zheng Jin, Xia Wu, Yu-zhang Chen, Xin-wen Wang, Sheng-dian Niu, Jun-qi Chen, Hai-rong Tang, Hong NKG2A is a NK cell exhaustion checkpoint for HCV persistence |
title | NKG2A is a NK cell exhaustion checkpoint for HCV persistence |
title_full | NKG2A is a NK cell exhaustion checkpoint for HCV persistence |
title_fullStr | NKG2A is a NK cell exhaustion checkpoint for HCV persistence |
title_full_unstemmed | NKG2A is a NK cell exhaustion checkpoint for HCV persistence |
title_short | NKG2A is a NK cell exhaustion checkpoint for HCV persistence |
title_sort | nkg2a is a nk cell exhaustion checkpoint for hcv persistence |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447531/ https://www.ncbi.nlm.nih.gov/pubmed/30944315 http://dx.doi.org/10.1038/s41467-019-09212-y |
work_keys_str_mv | AT zhangchao nkg2aisankcellexhaustioncheckpointforhcvpersistence AT wangxiaomei nkg2aisankcellexhaustioncheckpointforhcvpersistence AT lishuran nkg2aisankcellexhaustioncheckpointforhcvpersistence AT twelkmeyertrix nkg2aisankcellexhaustioncheckpointforhcvpersistence AT wangweihong nkg2aisankcellexhaustioncheckpointforhcvpersistence AT zhangshengyuan nkg2aisankcellexhaustioncheckpointforhcvpersistence AT wangshufeng nkg2aisankcellexhaustioncheckpointforhcvpersistence AT chenjizheng nkg2aisankcellexhaustioncheckpointforhcvpersistence AT jinxia nkg2aisankcellexhaustioncheckpointforhcvpersistence AT wuyuzhang nkg2aisankcellexhaustioncheckpointforhcvpersistence AT chenxinwen nkg2aisankcellexhaustioncheckpointforhcvpersistence AT wangshengdian nkg2aisankcellexhaustioncheckpointforhcvpersistence AT niujunqi nkg2aisankcellexhaustioncheckpointforhcvpersistence AT chenhairong nkg2aisankcellexhaustioncheckpointforhcvpersistence AT tanghong nkg2aisankcellexhaustioncheckpointforhcvpersistence |