Blood Journal
Leading the way in experimental and clinical research in hematology

Inositol tetrakisphosphate limits NK cell effector functions by controlling PI3K signaling

  1. Karsten Sauer1,*,
  2. Eugene Park2,*,
  3. Sabine Siegemund1,
  4. Anthony R. French3,
  5. Joseph A. Wahle4,
  6. Luise Sternberg1,
  7. Stephanie Rigaud1,
  8. A. Helena Jonsson4,
  9. Wayne M. Yokoyama4, and
  10. Yina H. Huang2
  1. 1Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA;
  2. 2Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO;
  3. 3Division of Pediatric Rheumatology, Department of Pediatrics, Washington University School of Medicine, St Louis, MO; and
  4. 4Howard Hughes Medical Institute, Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO

Key Points

  • By producing soluble IP4, inositol-trisphosphate 3-kinase B promotes NK-cell terminal maturation but limits NK-cell effector functions.

  • IP4 acts in part by limiting phosphoinositide 3-kinase signaling via the effector kinase Akt downstream of NK-cell receptors.

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.

  • Submitted May 9, 2012.
  • Accepted November 12, 2012.
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