title: PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection.
abstract: Here, we report on the expression of programmed death (PD)-1 on human virus-specific CD8(+) T cells and the effect of manipulating signaling through PD-1 on the survival, proliferation, and cytokine function of these cells. PD-1 expression was found to be low on naive CD8(+) T cells and increased on memory CD8(+) T cells according to antigen specificity. Memory CD8(+) T cells specific for poorly controlled chronic persistent virus (HIV) more frequently expressed PD-1 than memory CD8(+) T cells specific for well-controlled persistent virus (cytomegalovirus) or acute (vaccinia) viruses. PD-1 expression was independent of maturational markers on memory CD8(+) T cells and was not directly associated with an inability to produce cytokines. Importantly, the level of PD-1 surface expression was the primary determinant of apoptosis sensitivity of virus-specific CD8(+) T cells. Manipulation of PD-1 led to changes in the ability of the cells to survive and expand, which, over several days, affected the number of cells expressing cytokines. Therefore, PD-1 is a major regulator of apoptosis that can impact the frequency of antiviral T cells in chronic infections such as HIV, and could be manipulated to improve HIV-specific CD8(+) T cell numbers, but possibly not all functions in vivo.
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Petrovas
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Casazza
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: William C
authors.initials: WC
authors.lastname: Adams
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Precopio
authors.forename: Timothy
authors.initials: T
authors.lastname: Schacker
authors.forename: Mario
authors.initials: M
authors.lastname: Roederer
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
mesh_terms: D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002470:Cell Survival; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D061026:Programmed Cell Death 1 Receptor
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor