title: Costimulatory molecule programmed death-1 in the cytotoxic response during chronic hepatitis C.
abstract: Hepatitis C virus (HCV)-specific CD8(+) T cells play an important role in the resolution of HCV infection. Nevertheless, during chronic hepatitis C these cells lack their effector functions and fail to control the virus. HCV has developed several mechanisms to escape immune control. One of these strategies is the up-regulation of negative co-stimulatory molecules such us programmed death-1 (PD-1). This molecule is up-regulated on intrahepatic and peripheral HCV-specific cytotoxic T cells during acute and chronic phases of the disease, whereas PD-1 expression is low in resolved infection. PD-1 expressing HCV-specific CD8(+) T cells are exhausted with impairment of several effector mechanisms, such as: type-1 cytokine production, expansion ability after antigen encounter and cytotoxic ability. However, PD-1 associated exhaustion can be restored by blocking the interaction between PD-1 and its ligand (PD-L1). After this blockade, HCV-specific CD8(+) T cells reacquire their functionality. Nevertheless, functional restoration depends on PD-1 expression level. High PD-1-expressing intrahepatic HCV-specific CD8(+) T cells do not restore their effector abilities after PD-1/PD-L1 blockade. The mechanisms by which HCV is able to induce PD-1 up-regulation to escape immune control are unknown. Persistent TCR stimulation by a high level of HCV antigens could favour early PD-1 induction, but the interaction between HCV core protein and gC1q receptor could also participate in this process. The PD-1/PD-L1 pathway modulation could be a therapeutic strategy, in conjunction with the regulation of others co-stimulatory pathways, in order to restore immune response against HCV to succeed in clearing the infection.
authors.affiliation: Translational Hepatology Unit, Guadalajara University Hospital, University of Alcalá, Donante de Sangre st, 19002 Guadalajara, Spain. jlarrubiam@meditex.es
authors.forename: Juan-Ramón
authors.initials: JR
authors.lastname: Larrubia
authors.forename: Selma
authors.initials: S
authors.lastname: Benito-Martínez
authors.forename: Joaquín
authors.initials: J
authors.lastname: Miquel
authors.forename: Miryam
authors.initials: M
authors.lastname: Calvino
authors.forename: Eduardo
authors.initials: E
authors.lastname: Sanz-de-Villalobos
authors.forename: Trinidad
authors.initials: T
authors.lastname: Parra-Cid
mesh_terms: D000208:Acute Disease; D015703:Antigens, CD / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D006526:Hepatitis C / Q000378:metabolism / Q000473:pathology; D019698:Hepatitis C, Chronic / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism* / Q000473:pathology; D014758:Viral Core Proteins / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D014758:Viral Core Proteins