Inositol tetrakisphosphate limits NK cell effector functions by controlling phosphoinositide 3-kinase signaling

Karsten Sauer, Eugene Park, Sabine Siegemund, Anthony R. French, Joseph A. Wahle, Luise Sternberg, Stephanie Rigaud, A. Helena Jonsson, Wayne M. Yokoyama and Yina H. Huang


NK cells have important functions in cancer immunosurveillance, bone marrow 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 upregulation of stress-induced ligands on pathogen-infected or tumor cells through invariant NK cell receptors (NKR), 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 PLCγ. Here, 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.