title: The combination of 4-1BBL and CD40L strongly enhances the capacity of dendritic cells to stimulate HIV-specific T cell responses.
abstract: One of the consequences of HIV infection is a progressive loss of T cell functions, resulting in decreased cytokine secretion and proliferation and an increased sensitivity to apoptosis. Therefore, successful therapeutic vaccination approaches should aim at restoring the functionality of existing HIV-specific T cells, as well as to efficiently induce potent, HIV-specific T cells from naïve T cells. In this study, we wanted to determine the stimulatory capacity of DCs coelectroporated with mRNA encoding for different costimulatory molecules of the TNFSF, together with HIV antigen-encoding mRNA. We show that DCs electroporated with 4-1BBL can enhance the proliferation, functionality, cytokine production, and survival of HIV-specific CD8(+) T cells. Furthermore, we are the first to show that a combination of 4-1BBL and CD40L overexpression on DCs dramatically enhances CD4(+) and CD8(+) T cell responses. Finally, we demonstrate that signaling through 4-1BB, but not through CD40, can alleviate the suppressive effect of Tregs on CD8(+) T cell proliferation. Thus, the combination of 4-1BBL and CD40L enhances HIV-specific CD8(+) T cell responses in a synergistic way, resulting in enhanced proliferation of CD4(+) and CD8(+) T cell subsets, an increased cytokine secretion, and a reduced sensitivity to Treg-mediated immune suppression.
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Brenda
authors.initials: B
authors.lastname: De Keersmaecker
authors.forename: Carlo
authors.initials: C
authors.lastname: Heirman
authors.forename: Jurgen
authors.initials: J
authors.lastname: Corthals
authors.forename: Christophe
authors.initials: C
authors.lastname: Empsen
authors.forename: Leo A
authors.initials: LA
authors.lastname: van Grunsven
authors.forename: Sabine D
authors.initials: SD
authors.lastname: Allard
authors.forename: Joeri
authors.initials: J
authors.lastname: Pen
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacor
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
authors.forename: Joeri L
authors.initials: JL
authors.lastname: Aerts
mesh_terms: D053330:4-1BB Ligand / Q000494:pharmacology*; D015153:Blotting, Western; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000494:pharmacology*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D006679:HIV Seropositivity; D006801:Humans; D008213:Lymphocyte Activation; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D053330:4-1BB Ligand; D019013:CD40 Antigens; D012333:RNA, Messenger; D023201:CD40 Ligand