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Optimal effector functions in human natural killer cells rely upon autocrine bone morphogenetic protein signaling

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Robson, Neil C. and Hidalgo, Laura and McAlpine, Tristan and Wei, Heng and Martínez, Víctor G. and Entrena Martínez, Ana and Melen, Gustavo J. and MacDonald, Andrew S. and Phythian-Adams, Alexander and Sacedón, Rosa and Maraskovsky, Eugene and Cebon, Jonathan and Ramírez, Manuel and Vicente, Ángeles and Varas, Alberto (2018) Optimal effector functions in human natural killer cells rely upon autocrine bone morphogenetic protein signaling. Cancer research, 74 (18). pp. 5019-5031. ISSN 0008-5472, ESSN: 1538-7445

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Official URL: http://cancerres.aacrjournals.org/content/74/18/5019



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 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.


Item Type:Article
Uncontrolled Keywords:Human killer cells; Bone morphogenetic; Protein Signaling
Subjects:Medical sciences > Medicine > Oncology
Medical sciences > Biology > Cytology
Medical sciences > Biology > Biochemistry
ID Code:47722
Deposited On:24 May 2018 11:20
Last Modified:25 May 2018 08:44

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