title: Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction.
abstract: The engagement of programmed death 1 (PD-1) to its ligands, PD-L1 and PD-L2, inhibits proliferation and cytokine production mediated by antibodies to CD3 (refs. 5,6,7). Blocking the PD-1-PD-L1 pathway in mice chronically infected with lymphocytic choriomeningitis virus restores the capacity of exhausted CD8(+) T cells to undergo proliferation, cytokine production and cytotoxic activity and, consequently, results in reduced viral load. During chronic HIV infection, HIV-specific CD8(+) T cells are functionally impaired, showing a reduced capacity to produce cytokines and effector molecules as well as an impaired capacity to proliferate. Here, we found that PD-1 was upregulated on HIV-specific CD8(+) T cells; PD-1 expression levels were significantly correlated both with viral load and with the reduced capacity for cytokine production and proliferation of HIV-specific CD8(+) T cells. Notably, cytomegalovirus (CMV)-specific CD8(+) T cells from the same donors did not upregulate PD-1 and maintained the production of high levels of cytokines. Blocking PD-1 engagement to its ligand (PD-L1) enhanced the capacity of HIV-specific CD8(+) T cells to survive and proliferate and led to an increased production of cytokines and cytotoxic molecules in response to cognate antigen. The accumulation of HIV-specific dysfunctional CD8(+) T cells in the infected host could prevent the renewal of a functionally competent HIV-specific CD8(+) repertoire.
authors.affiliation: Laboratoire d'Immunologie, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM) Saint-Luc, 264 Rene Levesque Est, Montréal, Québec H2X1P1, Canada.
authors.forename: Lydie
authors.initials: L
authors.lastname: Trautmann
authors.forename: Loury
authors.initials: L
authors.lastname: Janbazian
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chomont
authors.forename: Elias A
authors.initials: EA
authors.lastname: Said
authors.forename: Sylvain
authors.initials: S
authors.lastname: Gimmig
authors.forename: Benoit
authors.initials: B
authors.lastname: Bessette
authors.forename: Mohamed-Rachid
authors.initials: MR
authors.lastname: Boulassel
authors.forename: Eric
authors.initials: E
authors.lastname: Delwart
authors.forename: Homero
authors.initials: H
authors.lastname: Sepulveda
authors.forename: Robert S
authors.initials: RS
authors.lastname: Balderas
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Routy
authors.forename: Elias K
authors.initials: EK
authors.lastname: Haddad
authors.forename: Rafick-Pierre
authors.initials: RP
authors.lastname: Sekaly
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000096:biosynthesis*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D017252:CD3 Complex / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D015658:HIV Infections / Q000097:blood* / Q000378:metabolism*; D006801:Humans; D007107:Immune System / Q000473:pathology*; D007154:Immune System Diseases / Q000276:immunology* / Q000473:pathology; D016130:Immunophenotyping; D008969:Molecular Sequence Data; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D017252:CD3 Complex; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell