title: Interference with PD-L1/PD-1 co-stimulation during antigen presentation enhances the multifunctionality of antigen-specific T cells.
abstract: The release of cytokines by T cells strongly defines their functional activity in vivo. The ability to produce multiple cytokines has been associated with beneficial immune responses in cancer and infectious diseases, while their progressive loss is associated with T-cell exhaustion, senescence and anergy. Consequently, strategies that enhance the multifunctional status of T cells are a key for immunotherapy. Dendritic cells (DCs) are professional antigen presenting cells that regulate T-cell functions by providing positive and negative co-stimulatory signals. A key negative regulator of T-cell activity is provided by binding of programmed death-1 (PD-1) receptor on activated T cells, to its ligand PD-L1, expressed on DCs. We investigated the impact of interfering with PD-L1/PD-1 co-stimulation on the multifunctionality of T cells, by expression of the soluble extracellular part of PD-1 (sPD-1) or PD-L1 (sPD-L1) in human monocyte-derived DCs during antigen presentation. Expression, secretion and binding of these soluble molecules after mRNA electroporation were demonstrated. Modification of DCs with sPD-1 or sPD-L1 mRNA resulted in increased levels of the co-stimulatory molecule CD80 and a distinct cytokine profile, characterized by the secretion of IL-10 and TNF-α, respectively. Co-expression in DCs of sPD-1 and sPD-L1 with influenza virus nuclear protein 1 (Flu NP1) stimulated Flu NP1 memory T cells, with a significantly higher number of multifunctional T cells and increased cytokine secretion, while it did not induce regulatory T cells. These data provide a rationale for the inclusion of interfering sPD-1 or sPD-L1 in DC-based immunotherapeutic strategies.
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: J J
authors.initials: JJ
authors.lastname: Pen
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: B D
authors.initials: BD
authors.lastname: Keersmaecker
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Heirman
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Corthals
authors.affiliation: 1] Division of Infection and Immunity, Rayne Institute, University College London, London, UK [2] Navarrabiomed-FMS, Complejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Liechtenstein
authors.affiliation: 1] Division of Infection and Immunity, Rayne Institute, University College London, London, UK [2] Navarrabiomed-FMS, Complejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Escors
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Thielemans
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Breckpot
mesh_terms: D017951:Antigen Presentation; D060887:B7 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000235:genetics / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D060887:B7 Antigens; D018122:B7-1 Antigen; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; C079798:human parainfluenza virus type 1 nucleoprotein; D016753:Interleukin-10