title: Optimal effector functions in human natural killer cells rely upon autocrine bone morphogenetic protein signaling.
abstract: Natural killer (NK) cells are critical for innate tumor immunity due to their specialized ability to recognize and kill neoplastically transformed cells. However, NK cells require a specific set of cytokine-mediated signals to achieve optimal effector function. Th1-associated cytokines promote effector functions that are inhibited by the prototypic Th2 cytokine IL4 and the TGFβ superfamily members TGFβ1 and activin-A. Interestingly, the largest subgroup of the TGFβ superfamily are the bone morphogenetic proteins (BMP), but the effects of BMP signaling on NK cell effector functions have not been evaluated. Here, we demonstrate that blood-circulating NK cells express type I and II BMP receptors, BMP-2 and BMP-6 ligands, and phosphorylated isoforms of Smad-1/-5/-8, which mediate BMP family member signaling. In opposition to the inhibitory effects of TGFβ1 or activin-A, autocrine BMP signaling was supportive to NK cell function. Mechanistic investigations in cytokine and TLR-L-activated NK cells revealed that BMP signaling optimized IFNγ and global cytokine and chemokine production, phenotypic activation and proliferation, and autologous dendritic cell activation and target cytotoxicity. Collectively, our findings identify a novel auto-activatory pathway that is essential for optimal NK cell effector function, one that might be therapeutically manipulated to help eradicate tumors. Cancer Res; 74(18); 5019-31. ©2014 AACR.
authors.affiliation: Institute of Infection, Immunity & Inflammation, Sir Graeme Davis Building, The University of Glasgow, Scotland.
authors.forename: Neil C
authors.initials: NC
authors.lastname: Robson
authors.affiliation: Department of Cell Biology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Hidalgo
authors.affiliation: Ludwig Institute for Cancer Research, Austin Health, Heidelberg, VIC, 3084, Australia.
authors.forename: Tristan
authors.initials: T
authors.lastname: Mc Alpine
authors.affiliation: Ludwig Institute for Cancer Research, Austin Health, Heidelberg, VIC, 3084, Australia.
authors.forename: Heng
authors.initials: H
authors.lastname: Wei
authors.affiliation: Department of Cell Biology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain.
authors.forename: Víctor G
authors.initials: VG
authors.lastname: Martínez
authors.affiliation: Department of Cell Biology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Entrena
authors.affiliation: Department of Oncohematology, Niño Jesús Hospital, 28009 Madrid, Spain.
authors.forename: Gustavo J
authors.initials: GJ
authors.lastname: Melen
authors.affiliation: MCCIR, Core Technology Facility, The University of Manchester, Manchester, M13 9NT, UK.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: MacDonald
authors.affiliation: MCCIR, Core Technology Facility, The University of Manchester, Manchester, M13 9NT, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Phythian-Adams
authors.affiliation: Department of Cell Biology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Sacedón
authors.affiliation: CSL Limited, Parkville, Melbourne, VIC, 3052, Australia.
authors.forename: Eugene
authors.initials: E
authors.lastname: Maraskovsky
authors.affiliation: Ludwig Institute for Cancer Research, Austin Health, Heidelberg, VIC, 3084, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
authors.affiliation: Department of Oncohematology, Niño Jesús Hospital, 28009 Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ramírez
authors.affiliation: Department of Cell Biology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: Vicente
authors.affiliation: Department of Cell Biology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Varas
mesh_terms: D019898:Autocrine Communication; D052004:Bone Morphogenetic Protein Receptors / Q000276:immunology / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction
chemical_list: D019485:Bone Morphogenetic Proteins; D012333:RNA, Messenger; D052004:Bone Morphogenetic Protein Receptors