KLRG1 Negatively Regulates Natural Killer Cell Functions through the Akt Pathway in Individuals with Chronic Hepatitis C Virus Infection

Abstract

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-␥) 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-␥ production but increased apoptosis compared to KLRG1؊ NK cells, particularly in HCV-infected individuals. Importantly, blockade of KLRG1 signaling significantly recovered the impaired IFN-␥ 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.

MicroRNA‐155 regulates interferon‐γ production in natural killer cells via Tim‐3 signalling in chronic hepatitis C virus infection

“…We have previously shown that Killer cell lectin‐like receptor subfamily G member 1 (KLRG‐1), a negative signalling molecule expressed on lymphocytes, is up‐regulated on NK cells from HCV‐infected patients; however, blocking KLRG‐1 signalling only partially restored NK cell functions . Here we demonstrated that both KLRG‐1 and Tim‐3 were up‐regulated and could co‐express on CD3 − CD56 + NK cells from HCV patients versus HS (Fig.…”

Viral (hepatitis C virus, hepatitis B virus, HIV) persistence and immune homeostasis

“…Importantly, blockade of KLRG1 signalling significantly recovered the impaired IFN-c production by NK cells from HCV-infected subjects. 122 We also demonstrated that KLRG1 was over-expressed on CD4 + T cells from HCV-infected, HBV vaccine non-responders compared with HBV vaccine responders. These results may partly explain why HBV vaccine responses in HCVinfected individuals are often blunted when compared with uninfected populations.…”

“…We demonstrated 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 HCV infection compared with subjects without infection. Importantly, blockade of KLRG1 signalling significantly recovered the impaired IFN‐γ production by NK cells from HCV‐infected subjects . We also demonstrated that KLRG1 was over‐expressed on CD4 + T cells from HCV‐infected, HBV vaccine non‐responders compared with HBV vaccine responders.…”

The Two Faces of Galectin-3: Roles in Various Pathological Conditions

“…It is believed that Galectin-3 interferes with binding to regulatory molecules on the cancer cell that serve as ligands for receptors of NK cells (96). Additionally, the results from Wang et al (97) suggested that expression of membrane KLRG1 receptors on NK cells impairs their activation and IFN-γ production, but increases apoptosis of these cells in chronic hepatitis C virus infection.…”