Journal
JOURNAL OF VIROLOGY
Volume 87, Issue 21, Pages 11626-11636Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01515-13
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Funding
- NIH NIDDK grant [R01DK093526]
- NIAID grant [1R15AI10382801]
- Guanghua Foundation of Xian Jiaotong University, China
- Beijing 302 Hospital, Beijing, China
- Guangzhou Municipal Health Bureau, China
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In this study, we demonstrate that killer cell lectin-like receptor subfamily G member 1 (KLRG1), a transmembrane protein preferentially expressed on T cells, is highly expressed on CD56(+) NK cells, which are significantly reduced in their numbers and functions in the peripheral blood of patients with chronic hepatitis C virus (HCV) infection compared to subjects without infection. KLRG1 expression is also upregulated on healthy NK cells exposed to Huh-7 hepatocytes infected with HCV in vitro. Importantly, the expression levels of KLRG1 are inversely associated with the capacity of NK cells to proliferate and to produce gamma interferon (IFN-gamma) but positively associated with apoptosis of NK cells in response to inflammatory cytokine stimulation. KLRG1(+) NK cells, including CD56(bright) and CD56(dim) subsets, exhibit impaired cell activation and IFN-gamma production but increased apoptosis compared to KLRG1(+) NK cells, particularly in HCV-infected individuals. Importantly, blockade of KLRG1 signaling significantly recovered the impaired IFN-gamma production by NK cells from HCV-infected subjects. Blockade of KLRG1 also enhanced the impaired phosphorylation of Akt (Ser473) in NK cells from HCV-infected subjects. Taken together, these results indicate that KLRG1 negatively regulates NK cell numbers and functions via the Akt pathway, thus providing a novel marker and therapeutic target for HCV infection.
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