title: 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-γ) 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-γ production but increased apoptosis compared to KLRG1(-) NK cells, particularly in HCV-infected individuals. Importantly, blockade of KLRG1 signaling significantly recovered the impaired IFN-γ 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.
authors: Department of Internal Medicine, Division of Infectious Diseases, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA.
authors: Jia M
authors: JM
authors: Wang
authors: Yong Q
authors: YQ
authors: Cheng
authors: Lei
authors: L
authors: Shi
authors: Ruo S
authors: RS
authors: Ying
authors: Xiao Y
authors: XY
authors: Wu
authors: Guang Y
authors: GY
authors: Li
authors: Jonathan P
authors: JP
authors: Moorman
authors: Zhi Q
authors: ZQ
authors: Yao
mesh_terms: D017209:Apoptosis; D019002:CD56 Antigen / Q000032:analysis; D049109:Cell Proliferation; D005260:Female; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000737:chemistry / Q000276:immunology*; D037181:Lectins, C-Type / Q000378:metabolism*; D008297:Male; D011971:Receptors, Immunologic; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D019002:CD56 Antigen; C113413:KLRG1 protein, human; D037181:Lectins, C-Type; C522918:NCAM1 protein, human; D011971:Receptors, Immunologic; D015534:Trans-Activators; D007371:Interferon-gamma
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