title: Differential regulation of T and B lymphocytes by PD-1 and SOCS-1 signaling in hepatitis C virus-associated non-Hodgkin's lymphoma.
abstract: HCV infection is associated with immune dysregulation and B cell Non-Hodgkins lymphoma (HCV-NHL). We have previously shown in vitro that HCV core protein differentially regulates T and B cell functions through two negative signaling pathways, programmed death-1 (PD-1) and suppressor of cytokine signaling-1 (SOCS-1). In this report, we performed a detailed immunologic analysis of T and B cell functions in the setting of HCV-NHL. We observed that T cells isolated from patients with HCV-NHL exhibited an exhausted phenotype including decreased expression of viral-specific and non-specific activation markers; whereas B cells exhibited an activated phenotype including over-expression of cell activation markers and immunoglobulins compared to healthy subjects. Individuals with HCV alone or NHL alone exhibited abnormal T and B cell phenotypes, but to a lesser extent compared to HCV-NHL. This differential activation of T and B lymphocytes was inversely associated with the expression of PD-1 and SOCS-1. Interestingly, blocking PD-1 during TCR activation inhibited SOCS-1 gene expression, suggesting that these regulatory pathways are linked in T cells. Importantly, blocking PD-1 also restored the impaired T cell functions observed in the setting of HCV-NHL. These results support a coordinated mechanism by which HCV might cause immune dysregulation that is associated to HCV-NHL.
authors.affiliation: Medical Service, James H. Quillen VA Medical Center, Johnson City, TN, 37684, USA. Yao@etsu.edu
authors.forename: Zhi Q
authors.initials: ZQ
authors.lastname: Yao
authors.forename: Lei
authors.initials: L
authors.lastname: Ni
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Cheng J
authors.initials: CJ
authors.lastname: Ma
authors.forename: Chun L
authors.initials: CL
authors.lastname: Zhang
authors.forename: Zhi P
authors.initials: ZP
authors.lastname: Dong
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Frazier
authors.forename: Xiao Y
authors.initials: XY
authors.lastname: Wu
authors.forename: Penny
authors.initials: P
authors.lastname: Thayer
authors.forename: Thomas
authors.initials: T
authors.lastname: Borthwick
authors.forename: Xin Y
authors.initials: XY
authors.lastname: Chen
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Moorman
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic; D016174:Hepacivirus / Q000276:immunology; D006526:Hepatitis C / Q000150:complications*; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000150:complications / Q000276:immunology; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D050826:Suppressor of Cytokine Signaling Proteins