Decision letter for "Styk1 expression is a hallmark of murine NK cells and other NK1.1 + subsets but is dispensable for NK cell development and effector functions"

2019 ◽  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Cell Development ◽  
Effector Functions

scholarly journals The p110δ of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation

2008 ◽  
Vol 205 (10) ◽  
pp. 2419-2435 ◽  
Author(s):  
Hailong Guo ◽  
Asanga Samarakoon ◽  
Bart Vanhaesebroeck ◽  
Subramaniam Malarkannan
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Cell Receptor ◽  
Cell Development ◽  
Effector Functions ◽  
Antiviral Responses

Phosphatidylinositol 3-kinases (PI3Ks) play a critical role in regulating B cell receptor– and T cell receptor–mediated signaling. However, their role in natural killer (NK) cell development and functions is not well understood. Using mice expressing p110δD910A, a catalytically inactive p110δ, we show that these mice had reduced NK cellularity, defective Ly49C and Ly49I NK subset maturation, and decreased CD27High NK numbers. p110δ inactivation marginally impaired NK-mediated cytotoxicity against tumor cells in vitro and in vivo. However, NKG2D, Ly49D, and NK1.1 receptor–mediated cytokine and chemokine generation by NK cells was severely affected in these mice. Further, p110δD910A/D910A NK cell–mediated antiviral responses through natural cytotoxicity receptor 1 were reduced. Analysis of signaling events demonstrates that p110δD910A/D910A NK cells had a reduced c-Jun N-terminal kinase 1/2 phosphorylation in response to NKG2D-mediated activation. These results reveal a previously unrecognized role of PI3K-p110δ in NK cell development and effector functions.

scholarly journals The Role of microRNAs in NK Cell Development and Function

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2020
Author(s):  
Arash Nanbakhsh ◽  
Subramaniam Malarkannan
Keyword(s):  
Nk Cells ◽  
Cellular Therapy ◽  
Nk Cell ◽  
Cell Development ◽  
Clinical Use ◽  
Effector Functions ◽  
Genetic Manipulations ◽  
Cytotoxic Proteins ◽  
And Function

The clinical use of natural killer (NK) cells is at the forefront of cellular therapy. NK cells possess exceptional antitumor cytotoxic potentials and can generate significant levels of proinflammatory cytokines. Multiple genetic manipulations are being tested to augment the anti-tumor functions of NK cells. One such method involves identifying and altering microRNAs (miRNAs) that play essential roles in the development and effector functions of NK cells. Unique miRNAs can bind and inactivate mRNAs that code for cytotoxic proteins. MicroRNAs, such as the members of the Mirc11 cistron, downmodulate ubiquitin ligases that are central to the activation of the obligatory transcription factors responsible for the production of inflammatory cytokines. These studies reveal potential opportunities to post-translationally enhance the effector functions of human NK cells while reducing unwanted outcomes. Here, we summarize the recent advances made on miRNAs in murine and human NK cells and their relevance to NK cell development and functions.

scholarly journals Styk1 expression is a hallmark of murine NK cells and other NK1.1 + subsets but is dispensable for NK‐cell development and effector functions

2019 ◽  
Vol 49 (5) ◽  
pp. 677-685 ◽  
Author(s):  
Sébastien Fauteux‐Daniel ◽  
Fabrice Faure ◽  
Marie Marotel ◽  
Clair Geary ◽  
Cécile Daussy ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Cell Development ◽  
Effector Functions

scholarly journals Inositol tetrakisphosphate limits NK cell effector functions by controlling PI3K signaling

Blood ◽  
2013 ◽  
Vol 121 (2) ◽  
pp. 286-297 ◽  
Author(s):  
Karsten Sauer ◽  
Eugene Park ◽  
Sabine Siegemund ◽  
Anthony R. French ◽  
Joseph A. Wahle ◽  
...  
Keyword(s):  
Nk Cells ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Cell Development ◽  
Effector Functions ◽  
Loss Of Self ◽  
Inositol Tetrakisphosphate ◽  
Stressed Cells ◽  
Second Messenger Pathways ◽  
And Function

Abstract Natural killer (NK) cells have important functions in cancer immunosurveillance, BM allograft rejection, fighting infections, tissue homeostasis, and reproduction. NK cell–based therapies are promising treatments for blood cancers. Overcoming their currently limited efficacy requires a better understanding of the molecular mechanisms controlling NK cell development and dampening their effector functions. NK cells recognize the loss of self-antigens or up-regulation of stress-induced ligands on pathogen-infected or tumor cells through invariant NK cell receptors (NKRs), and then kill such stressed cells. Two second-messenger pathways downstream of NKRs are required for NK cell maturation and effector responses: PIP3 generation by PI3K and generation of diacylglycerol and IP3 by phospholipase-Cγ (PLCγ). In the present study, we identify a novel role for the phosphorylated IP3 metabolite inositol (1,3,4,5)tetrakisphosphate (IP4) in NK cells. IP4 promotes NK cell terminal differentiation and acquisition of a mature NKR repertoire. However, in mature NK cells, IP4 limits NKR-induced IFNγ secretion, granule exocytosis, and target-cell killing, in part by inhibiting the PIP3 effector-kinase Akt. This identifies IP4 as an important novel regulator of NK cell development and function and expands our understanding of the therapeutically important mechanisms dampening NK cell responses. Our results further suggest that PI3K regulation by soluble IP4 is a broadly important signaling paradigm.

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