Inositol tetrakisphosphate limits NK cell effector functions by controlling PI3K signaling
| Autor: | Luise Sternberg, Yina H. Huang, A. Helena Jonsson, Karsten Sauer, Anthony R. French, Joseph A. Wahle, Wayne M. Yokoyama, Stephanie Rigaud, Sabine Siegemund, Eugene Park |
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| Rok vydání: | 2013 |
| Předmět: |
Mice
Knockout Lymphokine-activated killer cell Cell growth Effector Inositol Phosphates Immunology Receptors Cytoplasmic and Nuclear Cell Biology Hematology Biology Lymphocyte Activation Biochemistry Cell biology Killer Cells Natural Mice Phosphatidylinositol 3-Kinases Interleukin 21 Interleukin 12 Animals Signal transduction PI3K/AKT/mTOR pathway Tissue homeostasis Immunobiology Signal Transduction |
| Zdroj: | Blood. 121:286-297 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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