title: Activin-A: a novel dendritic cell-derived cytokine that potently attenuates CD40 ligand-specific cytokine and chemokine production.
abstract: Activin-A is a transforming growth factor-beta (TGF-beta) superfamily member that plays a pivotal role in many developmental and reproductive processes. It is also involved in neuroprotection, apoptosis of tumor and some immune cells, wound healing, and cancer. Its role as an immune-regulating protein has not previously been described. Here we demonstrate for the first time that activin-A has potent autocrine effects on the capacity of human dendritic cells (DCs) to stimulate immune responses. Human monocyte-derived DCs (MoDCs) and the CD1c(+) and CD123(+) peripheral blood DC populations express both activin-A and the type I and II activin receptors. Furthermore, MoDCs and CD1c(+) myeloid DCs rapidly secrete high levels of activin-A after exposure to bacteria, specific toll-like receptor (TLR) ligands, or CD40 ligand (CD40L). Blocking autocrine activin-A signaling in DCs using its antagonist, follistatin, enhanced DC cytokine (IL-6, IL-10, IL-12p70, and tumor necrosis factor-alpha [TNF-alpha]) and chemokine (IL-8, IP-10, RANTES, and MCP-1) production during CD40L stimulation, but not TLR-4 ligation. Moreover, antagonizing DC-derived activin-A resulted in significantly enhanced expansion of viral antigen-specific effector CD8(+) T cells. These findings establish an immune-regulatory role for activin-A in DCs, highlighting the potential of antagonizing activin-A signaling in vivo to enhance vaccine immunogenicity.
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Heidelberg, Victoria 3084, Australia. neil.robson@ludwig.edu.au
authors.forename: Neil C
authors.initials: NC
authors.lastname: Robson
authors.forename: David J
authors.initials: DJ
authors.lastname: Phillips
authors.forename: Tristan
authors.initials: T
authors.lastname: McAlpine
authors.forename: Amanda
authors.initials: A
authors.lastname: Shin
authors.forename: Suzanne
authors.initials: S
authors.lastname: Svobodova
authors.forename: Tracey
authors.initials: T
authors.lastname: Toy
authors.forename: Vinochani
authors.initials: V
authors.lastname: Pillay
authors.forename: Naomi
authors.initials: N
authors.lastname: Kirkpatrick
authors.forename: Damien
authors.initials: D
authors.lastname: Zanker
authors.forename: Kathy
authors.initials: K
authors.lastname: Wilson
authors.forename: Imke
authors.initials: I
authors.lastname: Helling
authors.forename: Heng
authors.initials: H
authors.lastname: Wei
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
authors.forename: Eugene
authors.initials: E
authors.lastname: Maraskovsky
mesh_terms: D028341:Activins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology* / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D018925:Chemokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes; D038681:Follistatin / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D055435:Myostatin; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: C525809:BMP4 protein, human; C525819:BMP7 protein, human; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D018925:Chemokines; D000939:Epitopes; D038681:Follistatin; D008070:Lipopolysaccharides; C525911:MSTN protein, human; D055435:Myostatin; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; C422405:activin A; D028341:Activins; D023201:CD40 Ligand