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Title: Optimal effector functions in human natural killer cells rely upon autocrine bone morphogenetic protein signaling.
Austin Authors: Robson, Neil C;Hidalgo, Laura;McAlpine, Tristan;Wei, Heng;Martínez, Víctor G;Entrena, Ana;Melen, Gustavo J;MacDonald, Andrew S;Phythian-Adams, Alexander;Sacedón, Rosa;Maraskovsky, Eugene;Cebon, Jonathan S ;Ramírez, Manuel;Vicente, Angeles;Varas, Alberto
Affiliation: CSL Limited, Parkville, Melbourne, Victoria, Australia
Ludwig Institute for Cancer Research, Austin Health, Heidelberg, Victoria, Australia
Institute of Infection, Immunity and Inflammation, The University of Glasgow, Glasgow, United Kingdom.
Department of Cell Biology, Faculty of Medicine, Complutense University, Madrid, Spain.
Department of Oncohematology, Niño Jesús Hospital, Madrid, Spain.
MCCIR, Core Technology Facility, The University of Manchester, Manchester, United Kingdom.
Department of Cell Biology, Faculty of Medicine, Complutense University, Madrid, Spain.
Issue Date: 18-Jul-2014
Publication information: Cancer Research 2014; 74(18): 5019-31
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.
Gov't Doc #: 25038228
DOI: 10.1158/0008-5472.CAN-13-2845
Type: Journal Article
Subjects: Autocrine Communication
Bone Morphogenetic Protein Receptors.immunology.metabolism
Bone Morphogenetic Proteins.biosynthesis.genetics.immunology.metabolism
Cell Differentiation.immunology
Killer Cells, Natural.immunology.metabolism
RNA, Messenger.biosynthesis.genetics
Signal Transduction
Appears in Collections:Journal articles

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