The paradox of NKp46+ natural killer cells: drivers of severe hepatitis C virus-induced pathology but in-vivo resistance to interferon treatment

Pembroke, Thomas ORCID: https://orcid.org/0000-0002-2600-2034, Christian, Adam, Jones, Emma, Hills, Robert Kerrin ORCID: https://orcid.org/0000-0003-0166-0062, Wang, Edward Chung Yern ORCID: https://orcid.org/0000-0002-2243-4964, Gallimore, Awen Myfanwy ORCID: https://orcid.org/0000-0001-6675-7004 and Godkin, Andrew James ORCID: https://orcid.org/0000-0002-1910-7567 2013. The paradox of NKp46+ natural killer cells: drivers of severe hepatitis C virus-induced pathology but in-vivo resistance to interferon treatment. Gut n/a 10.1136/gutjnl-2013-304472

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Abstract

Objective: There is evidence that natural killer (NK) cells help control persistent viral infections including hepatitis C virus (HCV). The phenotype and function of blood and intrahepatic NK cells, in steady state and after interferon (IFN) α treatment has not been fully elucidated. Design: We performed a comparison of NK cells derived from blood and intrahepatic compartments in multiple paired samples from patients with a variety of chronic liver diseases. Furthermore, we obtained serial paired samples from an average of five time points in HCV patients treated with IFNα. Results: Liver NK cells demonstrate a distinct activated phenotype compared to blood manifested as downregulation of the NK cell activation receptors CD16, NKG2D, and NKp30; with increased spontaneous degranulation and IFN production. In contrast, NKp46 expression was not downregulated. Indeed, NKp46-rich NK populations were the most activated, correlating closely with the severity of liver inflammation. Following initiation of IFNα treatment there was a significant increase in the proportion of intrahepatic NK cells at days 1 and 3. NKp46-rich NK populations demonstrated no reserve activation capacity with IFNα treatment and were associated with poor viral control on treatment and treatment failure. Conclusions: NKp46 marks out pathologically activated NK cells, which may result from a loss of homeostatic control of activating receptor expression in HCV. Paradoxically these pathological NK cells do not appear to be involved in viral control in IFNα-treated individuals and, indeed, predict slower rates of viral clearance.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > QR Microbiology > QR355 Virology R Medicine > RB Pathology
Additional Information:	Online publication date: 11 May 2013.
Publisher:	BMJ Publishing Group Ltd
ISSN:	0017-5749
Date of First Compliant Deposit:	30 March 2016
Last Modified:	25 Sep 2023 08:47
URI:	https://orca.cardiff.ac.uk/id/eprint/48533

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