NKG2A is a NK Cell Exhaustion Checkpoint for HCV Persistence

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Apr 5

PMID 30944315

Citations 77

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

Affiliations

Soon will be listed here.

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 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.

Citing Articles

The Malignant Transformation of Viral Hepatitis to Hepatocellular Carcinoma: Mechanisms and Interventions.

Yuan H, Xu R, Li S, Zheng M, Tong Q, Xiang M MedComm (2020). 2025; 6(3):e70121.

PMID: 40060195 PMC: 11890166. DOI: 10.1002/mco2.70121.

NK cell exhaustion in Wilson's disease revealed by single-cell RNA sequencing predicts the prognosis of cholecystitis.

Jin Y, Xing J, Dai C, Jin L, Zhang W, Tao Q Elife. 2025; 13.

PMID: 39854622 PMC: 11684787. DOI: 10.7554/eLife.98867.

Systems immunology integrates the complex endotypes of recessive dystrophic epidermolysis bullosa.

Hirt N, Manchon E, Chen Q, Delaroque C, Corneau A, Hemon P Nat Commun. 2025; 16(1):664.

PMID: 39809737 PMC: 11733305. DOI: 10.1038/s41467-025-55934-7.

Mechanisms of Cbl-Mediated Ubiquitination of Proteins in T and Natural Killer Cells and Effects on Immune Cell Functions.

Nath P, Isakov N Life (Basel). 2025; 14(12.

PMID: 39768300 PMC: 11677474. DOI: 10.3390/life14121592.

Immune Profile and MRI-Detected Cardiac Fibrosis and Edema in Hypertensive and Non-Hypertensive Patients with COVID-19.

Moll-Bernardes R, Camargo G, Silvestre-Sousa A, Barroso J, Ferreira J, Tortelly M J Clin Med. 2024; 13(23).

PMID: 39685774 PMC: 11642154. DOI: 10.3390/jcm13237317.

References

Wilson E, Yamada D, Elsaesser H, Herskovitz J, Deng J, Cheng G . Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science. 2013; 340(6129):202-7. PMC: 3704950. DOI: 10.1126/science.1235208. View

McMahan R, Golden-Mason L, Nishimura M, McMahon B, Kemper M, Allen T . Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. J Clin Invest. 2010; 120(12):4546-57. PMC: 2994339. DOI: 10.1172/JCI43127. View

. Sensory neurons regulate the effector functions of CD8(+) T cells in controlling HSV-1 latency ex vivo. Immunity. 2006; 24(5):657. DOI: 10.1016/j.immuni.2006.05.009. View

Peng H, Wisse E, Tian Z . Liver natural killer cells: subsets and roles in liver immunity. Cell Mol Immunol. 2015; 13(3):328-36. PMC: 4856807. DOI: 10.1038/cmi.2015.96. View

Rehermann B . Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat Med. 2013; 19(7):859-68. PMC: 4482132. DOI: 10.1038/nm.3251. View

Fisicaro P, Valdatta C, Massari M, Loggi E, Ravanetti L, Urbani S . Combined blockade of programmed death-1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV. Gastroenterology. 2012; 143(6):1576-1585.e4. DOI: 10.1053/j.gastro.2012.08.041. View

Cavanaugh V, Raulet D, Campbell A . Upregulation of CD94/NKG2A receptors and Qa-1b ligand during murine cytomegalovirus infection of salivary glands. J Gen Virol. 2007; 88(Pt 5):1440-1445. DOI: 10.1099/vir.0.82444-0. View

Zuniga E, Macal M, Lewis G, Harker J . Innate and Adaptive Immune Regulation During Chronic Viral Infections. Annu Rev Virol. 2016; 2(1):573-97. PMC: 4785831. DOI: 10.1146/annurev-virology-100114-055226. View

Han Q, Xu C, Wu C, Zhu W, Yang R, Chen X . Compensatory mutations in NS3 and NS5A proteins enhance the virus production capability of hepatitis C reporter virus. Virus Res. 2009; 145(1):63-73. DOI: 10.1016/j.virusres.2009.06.005. View

10.

Jinushi M, Takehara T, Tatsumi T, Kanto T, Miyagi T, Suzuki T . Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol. 2004; 173(10):6072-81. DOI: 10.4049/jimmunol.173.10.6072. View

11.

Ramsuran V, Naranbhai V, Horowitz A, Qi Y, Martin M, Yuki Y . Elevated expression impairs HIV control through inhibition of NKG2A-expressing cells. Science. 2018; 359(6371):86-90. PMC: 5933048. DOI: 10.1126/science.aam8825. View

12.

Waggoner S, Cornberg M, Selin L, Welsh R . Natural killer cells act as rheostats modulating antiviral T cells. Nature. 2011; 481(7381):394-8. PMC: 3539796. DOI: 10.1038/nature10624. View

13.

Zehn D, Utzschneider D, Thimme R . Immune-surveillance through exhausted effector T-cells. Curr Opin Virol. 2016; 16:49-54. DOI: 10.1016/j.coviro.2016.01.002. View

14.

Chen J, Zhao Y, Zhang C, Chen H, Feng J, Chi X . Persistent hepatitis C virus infections and hepatopathological manifestations in immune-competent humanized mice. Cell Res. 2014; 24(9):1050-66. PMC: 4152738. DOI: 10.1038/cr.2014.116. View

15.

Watanabe H, Ohtsuka K, Kimura M, Ikarashi Y, Ohmori K, Kusumi A . Details of an isolation method for hepatic lymphocytes in mice. J Immunol Methods. 1992; 146(2):145-54. DOI: 10.1016/0022-1759(92)90223-g. View

16.

Khakoo S, Thio C, Martin M, Brooks C, Gao X, Astemborski J . HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science. 2004; 305(5685):872-4. DOI: 10.1126/science.1097670. View

17.

Vescovo T, Refolo G, Vitagliano G, Fimia G, Piacentini M . Molecular mechanisms of hepatitis C virus-induced hepatocellular carcinoma. Clin Microbiol Infect. 2016; 22(10):853-861. DOI: 10.1016/j.cmi.2016.07.019. View

18.

Martin Werner J, Heller T, Gordon A, Sheets A, Sherker A, Kessler E . Innate immune responses in hepatitis C virus-exposed healthcare workers who do not develop acute infection. Hepatology. 2013; 58(5):1621-31. PMC: 3688637. DOI: 10.1002/hep.26353. View

19.

Grebely J, Hajarizadeh B, Dore G . Direct-acting antiviral agents for HCV infection affecting people who inject drugs. Nat Rev Gastroenterol Hepatol. 2017; 14(11):641-651. DOI: 10.1038/nrgastro.2017.106. View

20.

Andre P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T . Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells. Cell. 2018; 175(7):1731-1743.e13. PMC: 6292840. DOI: 10.1016/j.cell.2018.10.014. View