title: Programmed death-1 affects suppressor of cytokine signaling-1 expression in T cells during hepatitis C infection.
abstract: Chronic hepatitis C virus (HCV) infection is associated with T-cell exhaustion that is mediated through upregulation of the PD-1 negative regulatory pathway. PD-1 expression is induced by HCV core protein, which also induces upregulation of SOCS-1, a key modulator that controls the Jak/STAT pathway regulating cytokine expression. To determine whether these two negative regulatory pathways are linked during T-cell signaling, SOCS-1 expression was examined by blocking the PD-1 pathway in T cells stimulated with anti-CD3/CD28 in the presence of HCV core protein. T cells isolated from healthy subjects or HCV-infected individuals were treated with anti-PD-1 or anti-PDL-1 antibodies in the presence or absence of HCV core protein, and SOCS-1 gene expression was detected by RT-PCR or immunoblotting, while T-cell functions were assayed by flow cytometric analyses. Both PD-1 and SOCS-1 gene expression were upregulated in healthy T cells exposed to HCV core protein, and blocking the PD-1 pathway downregulated SOCS-1 gene expression in these cells. Additionally, T cells isolated from chronically HCV-infected subjects exhibited increased PD-1 and SOCS-1 expression compared to healthy subjects, and SOCS-1 expression in T cells isolated from HCV-infected subjects was also inhibited by blocking PD-1 signaling; this in turn enhanced the phosphorylation of STAT-1, and improved the impaired T-cell proliferation observed in the setting of HCV infection. These data demonstrate that PD-1 and SOCS-1 are linked in dysregulating T-cell signaling during HCV infection, and their cross-talk may coordinately inhibit T-cell signaling pathways that lead to T-cell exhaustion during chronic viral infection.
authors.affiliation: Medical Service, Department of Veterans Affairs, James H. Quillen Veterans Administration Medical Center, Mountain Home, Tennessee, USA.
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Frazier
authors.forename: Chun L
authors.initials: CL
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Ni
authors.forename: Cheng J
authors.initials: CJ
authors.lastname: Ma
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiao Y
authors.initials: XY
authors.lastname: Wu
authors.forename: Antwan N
authors.initials: AN
authors.lastname: Atia
authors.forename: Zhi Q
authors.initials: ZQ
authors.lastname: Yao
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Moorman
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D015151:Immunoblotting; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000276:immunology*; D014758:Viral Core Proteins / Q000276:immunology
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus