ADCC-Mediated CD56dim NK Cell Responses Are Associated with Early HBsAg Clearance in Acute HBV Infection

Wen-Han Yu, Cormac Cosgrove, Christoph T. Berger, Patrick C. Cheney, Marina Krykbaeva, Arthur Y. Kim, Lia Lewis-Ximenez, Georg M. Lauer, Galit Alter

Abstract


Hepatitis B virus (HBV) affects up to 400 million people worldwide and accounts for approximately one million deaths per year from liver pathologies. Current treatment regimens are effective in suppressing viremia but usually have to be taken indefinitely, warranting research into new therapeutic approaches. Acute HBV infection in adults almost universally results in resolution of viremia, with the exception of immunocompromised persons, suggesting that the immune response can functionally cure or even eradicate HBV infection. Because immunophenotypic and functional studies have implicated a role for Natural Killer (NK) cells in HBV clearance during acute infection, we hypothesized that a distinct NK-cell profile exists in acute HBV infection that could provide information for the mechanism of HBV clearance. Using multivariate flow cytometry, we evaluated the expression of key activating and inhibitory receptors on NK cells, and their ability to respond to classic target cell lines. Multivariate analysis revealed selective perturbation of the CD56 dim NK-cell subset during acute infection, displaying low levels of NKp46+, NKp30+, CD160+ and CD161+ cells. Intriguingly, the CD56 dim NK-cell profile predicted time to HBV surface antigen (HBsAg) clearance from the blood, and distinct NK-cell profiles predicted early (NKp30, CD94, CD161) and late clearance (KIR3DL1, CD158a, perforin, NKp46). Finally, functional analysis demonstrated that early and late clearance tracked with elevated degranulation (CD107a) or IFNγ production, respectively, in response to ADCC-mediated activation. In conclusion, the cytolytic CD56dim NK-cell subset is selectively activated in acute HBV infection and displays distinct phenotypic and functional profiles associated with efficient and early control of HBV, implicating antibody-mediated cytolytic NK-cell responses in the early control and functional cure of HBV infection.


Keywords


HBV; NK cells; HBsAg; ADCC

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References


1. Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol. 2006;1:23-61. PubMed PMID: 18039107. doi: 10.1146/annurev.pathol.1.110304.100230

2. Grimm D, Heeg M, Thimme R. Hepatitis B virus: from immunobiology to immunotherapy. Clin Sci (Lond). 2013;124(2):77-85. PubMed PMID: 23013042. doi: 10.1042/CS20120169

3. Juszczyk J. Clinical course and consequences of hepatitis B infection. Vaccine. 2000;18 Suppl 1:S23-5. PubMed PMID: 10683539.

4. Gerlich WH. Medical virology of hepatitis B: how it began and where we are now. Virol J. 2013;10:239. PubMed PMID: 23870415. Pubmed Central PMCID: PMC3729363. doi: 10.1186/1743-422X-10-239

5. Rehermann B. Immune responses in hepatitis B virus infection. Semin Liver Dis. 2003;23(1):21-38. PubMed PMID: 12616448. doi: 10.1055/s-2003-37586

6. Reaiche GY, Le Mire MF, Mason WS, Jilbert AR. The persistence in the liver of residual duck hepatitis B virus covalently closed circular DNA is not dependent upon new viral DNA synthesis. Virology. 2010;406(2):286-92. PubMed PMID: 20705309. doi: 10.1016/j.virol.2010.07.013

7. Hoofnagle JH. Reactivation of hepatitis B. Hepatology. 2009;49(5 Suppl):S156-65. PubMed PMID: 19399803. doi: 10.1002/hep.22945

8. Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, Carson WE, Caligiuri MA. Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood. 2001;97(10):3146-51. PubMed PMID: 11342442.

9. Norris S, Collins C, Doherty DG, Smith F, McEntee G, Traynor O, Nolan N, Hegarty J, O'Farrelly C. Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J Hepatol. 1998;28(1):84-90. PubMed PMID: 9537869.

10. Caligiuri MA. Human natural killer cells. Blood. 2008;112(3):461-9. PubMed PMID: 18650461. Pubmed Central PMCID: PMC2481557. doi: 10.1182/blood-2007-09-077438

11. Dunn C, Peppa D, Khanna P, Nebbia G, Jones M, Brendish N, Lascar RM, Brown D, Gilson RJ, Tedder RJ, Dusheiko GM, Jacobs M, Klenerman P, Maini MK. Temporal analysis of early immune responses in patients with acute hepatitis B virus infection. Gastroenterology. 2009;137(4):1289-300. PubMed PMID: 19591831. doi: 10.1053/j.gastro.2009.06.054

12. Fisicaro P, Valdatta C, Boni C, Massari M, Mori C, Zerbini A, Orlandini A, Sacchelli L, Missale G, Ferrari C. Early kinetics of innate and adaptive immune responses during hepatitis B virus infection. Gut. 2009;58(7):974-82. PubMed PMID: 19201769. doi: 10.1136/gut.2008.163600

13. Kakimi K, Guidotti LG, Koezuka Y, Chisari FV. Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J Exp Med. 2000;192(7):921-30. PubMed PMID: 11015434. Pubmed Central PMCID: PMC2193313.

14. Li F, Wei H, Wei H, Gao Y, Xu L, Yin W, Sun R, Tian Z. Blocking the natural killer cell inhibitory receptor NKG2A increases activity of human natural killer cells and clears hepatitis B virus infection in mice. Gastroenterology. 2013;144(2):392-401. PubMed PMID: 23103614. 10.1053/j.gastro.2012.10.039

15. Peppa D, Gill US, Reynolds G, Easom NJ, Pallett LJ, Schurich A, Micco L, Nebbia G, Singh HD, Adams DH, Kennedy PT, Maini MK. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J Exp Med. 2013;210(1):99-114. PubMed PMID: 23254287. Pubmed Central PMCID: PMC3549717. doi: 10.1084/jem.20121172

16. Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 2008;9(5):495-502. PubMed PMID: 18425106. Pubmed Central PMCID: PMC2669298. doi: 10.1038/ni1581

17. Long EO, Kim HS, Liu D, Peterson ME, Rajagopalan S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol. 2013;31:227-58. PubMed PMID: 23516982. Pubmed Central PMCID: PMC3868343. doi: 10.1146/annurev-immunol-020711-075005

18. Cosgrove C, Berger CT, Kroy DC, Cheney PC, Ghebremichael M, Aneja J, Tomlinson M, Kim AY, Lauer GM, Alter G. Chronic HCV infection affects the NK cell phenotype in the blood more than in the liver. PLoS One. 2014;9(8):e105950. PubMed PMID: 25148254. Pubmed Central PMCID: PMC4141847. doi: 10.1371/journal.pone.0105950

19. Li HD, Xu QS, Liang YZ. Random frog: an efficient reversible jump Markov Chain Monte Carlo-like approach for variable selection with applications to gene selection and disease classification. Anal Chim Acta. 2012;740:20-6. PubMed PMID: 22840646. doi: 10.1016/j.aca.2012.06.031

20. Alter G, Jost S, Rihn S, Reyor LL, Nolan BE, Ghebremichael M, Bosch R, Altfeld M, Lauer GM. Reduced frequencies of NKp30+NKp46+, CD161+, and NKG2D+ NK cells in acute HCV infection may predict viral clearance. J Hepatol. 2011;55(2):278-88. PubMed PMID: 21168454. Pubmed Central PMCID: PMC3729214. doi: 10.1016/j.jhep.2010.11.030

21. Horowitz A, Stegmann KA, Riley EM. Activation of natural killer cells during microbial infections. Front Immunol. 2011;2:88. PubMed PMID: 22566877. Pubmed Central PMCID: PMC3342047. doi: 10.3389/fimmu.2011.00088

22. Fogli M, Costa P, Murdaca G, Setti M, Mingari MC, Moretta L, Moretta A, De Maria A. Significant NK cell activation associated with decreased cytolytic function in peripheral blood of HIV-1-infected patients. Eur J Immunol. 2004;34(8):2313-21. PubMed PMID: 15259029. doi: 10.1002/eji.200425251

23. Parsons MS, Tang CC, Jegaskanda S, Center RJ, Brooks AG, Stratov I, Kent SJ. Anti-HIV antibody-dependent activation of NK cells impairs NKp46 expression. J Immunol. 2014;192(1):308-15. PubMed PMID: 24319263. doi: 10.4049/jimmunol.1301247

24. Tjwa ET, van Oord GW, Hegmans JP, Janssen HL, Woltman AM. Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B. J Hepatol. 2011;54(2):209-18. PubMed PMID: 21095036. doi: 10.1016/j.jhep.2010.07.009

25. Ganem D, Prince AM. Hepatitis B virus infection--natural history and clinical consequences. N Engl J Med. 2004;350(11):1118-29. PubMed PMID: 15014185. doi: 10.1056/NEJMra031087

26. Lunemann S, Malone DF, Hengst J, Port K, Grabowski J, Deterding K, Markova A, Bremer B, Schlaphoff V, Cornberg M, Manns MP, Sandberg JK, Ljunggren HG, Bjorkstrom NK, Wedemeyer H. Compromised function of natural killer cells in acute and chronic viral hepatitis. J Infect Dis. 2014;209(9):1362-73. PubMed PMID: 24154737. 10.1093/infdis/jit561

27. Tranah GJ, Nalls MA, Katzman SM, Yokoyama JS, Lam ET, Zhao Y, Mooney S, Thomas F, Newman AB, Liu Y, Cummings SR, Harris TB, Yaffe K, Hlth A. Body Composition S. Mitochondrial DNA Sequence Variation Associated with Dementia and Cognitive Function in the Elderly. Journal of Alzheimers Disease. 2012;32(2):357-72. PubMed PMID: WOS:000309977800010. doi: 10.3233/jad-2012-120466

28. Hudspeth K, Donadon M, Cimino M, Pontarini E, Tentorio P, Preti M, Hong M, Bertoletti A, Bicciato S, Invernizzi P, Lugli E, Torzilli G, Gershwin ME, Mavilio D. Human liver-resident CD56(bright)/CD16(neg) NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways. J Autoimmun. 2016;66:40-50. PubMed PMID: 26330348. Pubmed Central PMCID: PMC4718768. doi: 10.1016/j.jaut.2015.08.011

29. Schlicht HJ, Schaller H. The secretory core protein of human hepatitis B virus is expressed on the cell surface. J Virol. 1989;63(12):5399-404. PubMed PMID: 2685356. Pubmed Central PMCID: PMC251207.

30. Alberti A, Diana S, Eddleston AL, Williams R. Changes in hepatitis B virus DNA polymerase in relation to the outcome of acute hepatitis type B. Gut. 1979;20(3):190-5. PubMed PMID: 437551. Pubmed Central PMCID: PMC1412290.


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Copyright (c) 2018 Wen-Han Yu, Cormac Cosgrove, Christoph T Berger, Patrick C Cheney, Marina Krykbaeva, Arthur Y Kim, Lia Lewis-Ximenez,.Georg M Lauer, Galit Alter

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