title: KLRG1 impairs CD4+ T cell responses via p16ink4a and p27kip1 pathways: role in hepatitis B vaccine failure in individuals with hepatitis C virus infection.
abstract: Coinfection of hepatitis B virus (HBV) with hepatitis C virus (HCV) is quite common, leading to an increase in morbidity and mortality. As such, HBV vaccination is recommended in HCV-infected individuals. However, HBV vaccine responses in HCV-infected individuals are often blunted compared with uninfected populations. The mechanism for this failure of vaccine response in HCV-infected subjects remains unclear. In this study, we investigated the expression and function of an inhibitory receptor, killer cell lectin-like receptor subfamily G member 1 (KLRG1), in the regulation of CD4(+) T cells and HBV vaccine responses during HCV infection. We demonstrated that KLRG1 was overexpressed on CD4(+) T cells from HCV-infected, HBV vaccine nonresponders compared with HBV vaccine responders. The capacity of CD4(+) T cells to proliferate and secrete IL-2 cytokine was inversely associated with the level of KLRG1 expression. Importantly, blocking KLRG1 signaling resulted in a significant improvement in CD4(+) T cell proliferation and IL-2 production in HCV-infected, HBV vaccine nonresponders in response to TCR stimulation. Moreover, blockade of KLRG1 increased the phosphorylation of Akt (Ser(473)) and decreased the expression of cell cycle inhibitors p16(ink4a) and p27(kip1), which subsequently enhanced the expression of cyclin-dependent kinase 2 and cyclin E. These results suggest that the KLRG1 pathway impairs CD4(+) T cell responses to neoantigen and induces a state of immune senescence in individuals with HCV infection, raising the possibility that blocking this negative-signaling pathway might improve HBV vaccine responses in the setting of chronic viral infection.
authors: Division of Infectious Diseases, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614;
authors: Lei
authors: L
authors: Shi
authors: Jia M
authors: JM
authors: Wang
authors: Jun P
authors: JP
authors: Ren
authors: Yong Q
authors: YQ
authors: Cheng
authors: Ruo S
authors: RS
authors: Ying
authors: Xiao Y
authors: XY
authors: Wu
authors: Shu M
authors: SM
authors: Lin
authors: Jeddidiah W D
authors: JW
authors: Griffin
authors: Guang Y
authors: GY
authors: Li
authors: Jonathan P
authors: JP
authors: Moorman
authors: Zhi Q
authors: ZQ
authors: Yao
mesh_terms: D000375:Aging / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D060085:Coinfection / Q000235:genetics / Q000276:immunology; D019927:Cyclin E / Q000235:genetics / Q000276:immunology; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000276:immunology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000276:immunology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology; D006509:Hepatitis B / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D017325:Hepatitis B Vaccines / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology* / Q000821:virology; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics* / Q000276:immunology; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics* / Q000276:immunology
chemical_list: D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017325:Hepatitis B Vaccines; D007376:Interleukin-2; C113413:KLRG1 protein, human; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D015534:Trans-Activators; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051057:Proto-Oncogene Proteins c-akt; D051357:Cyclin-Dependent Kinase 2