RT Journal Article
T1 Optimal effector functions in human natural killer cells rely upon autocrine bone morphogenetic protein signaling
A1 Robson, Neil C.
A1 Hidalgo, Laura
A1 McAlpine, Tristan
A1 Wei, Heng
A1 Martínez, Víctor G.
A1 Entrena Martínez, Ana
A1 Melen, Gustavo J.
A1 MacDonald, Andrew S.
A1 Phythian-Adams, Alexander
A1 Sacedón, Rosa
A1 Maraskovsky, Eugene
A1 Cebon, Jonathan
A1 Ramírez, Manuel
A1 Vicente, Ángeles
A1 Varas, Alberto
AB 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 TGFb superfamily members TGFb1 and activin-A. Interestingly, the largest subgroup of the TGFb 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 TGFb1 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 IFNg 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.
PB American Association for Cancer Research
SN 0008-5472, ESSN: 1538-7445
YR 2018
FD 2018-09
LK https://hdl.handle.net/20.500.14352/12142
UL https://hdl.handle.net/20.500.14352/12142
LA eng
NO Ministerio de Economía y Competitividad (MINECO)
NO Ministerio de Educación, Cultura y Deporte (MECD)
NO Comunidad de Madrid
NO Instituto de Salud Carlos III
NO Australian National Health and Medical Research Council (NHMRC)
NO Ludwig Institute for Cancer Research
NO University of Glasgow
DS Docta Complutense
RD 3 may 2024