Soluble IP4 limits NK cell effector functions by controlling PI3K signaling (1013.1)

Abstract

NK cells are important for cancer immunosurveillance, bone marrow allograft rejection, fighting infections and reproduction. Overcoming their limited efficacy in cancer immunotherapies requires a better understanding of the mechanisms limiting NK cell effector functions. NK cells recognize and kill pathogen‐infected or tumor cells through NK cell receptors (NKR). Two second‐messenger downstream pathways are required for NK cell maturation and function: PIP3‐generation by PI3K, and generation of DAG and IP3 by PLCγ. IP3 has a key signaling role by mobilizing Calcium, but can also be converted into soluble inositol(1,3,4,5)tetrakisphosphate (IP4). IP4 can act as a soluble analog of the PI3K lipid‐product phosphatidylinositol(3,4,5)trisphosphate (PIP3) and control PIP3‐mediated signaling protein membrane recruitment and activation in thymocytes and granulocytes. Here, we show published and unpublished data which suggest that IP4 limits NKR induced IFNγ secretion, granule exocytosis and target‐cell clearance, in part by inhibiting the PIP3 effector‐kinase Akt in NK cells. This identifies IP4 as an important novel regulator of NK cell 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.Grant Funding Source: Supported by NIH grants AI070845, GM088647, AI089805 & Leukemia & Lymphoma Society Award 1440‐11