Phosphoinositide-3-Kinase Signaling in Human Natural Killer Cells: New Insights from Primary Immunodeficiency

Abstract

Human natural killer (NK) cells play a critical role in the control of viral infections and malignancy. Their importance in human health and disease is illustrated by severe viral infections in patients with primary immunodeficiencies that affect NK cell function and/or development. The recent identification of patients with phosphoinositide-3-kinase (PI3K)-signaling pathway mutations that can cause primary immunodeficiency provides valuable insight into the role that PI3K signaling plays in human NK cell maturation and lytic function. There is a rich literature that demonstrates a requirement for PI3K in multiple key aspects of NK cell biology, including development/maturation, homing, priming, and function. Here, I briefly review these previous studies and place them in context with recent findings from the study of primary immunodeficiency patients, particularly those with hyperactivating mutations in PI3Kδ signaling.

Keywords: human natural killer cells; natural killer cell biology; natural killer cell cytotoxicity; natural killer cell development; phosphoinositide-3-kinase signaling; primary immunodeficiency.

Figure 1

The effect of activated PI3K delta syndrome (APDS)-causing mutations on human natural killer (NK) cell function. Common mutations in p110δ that lead to disease are shown, including those that lead to loss of negative regulation by the p85α-regulatory subunit (E525K, N334K), and the E1021K mutation that leads to constitutive membrane association. Phosphoinositide-3-kinase (PI3K) p110δ catalyzes the conversion of PtdIns(3,4)P2 to PtdIns(3,4,5)P3 at the cell membrane, a reaction that is negatively regulated by phosphatase and tensin homolog (PTEN). Gain-of-function mutations in PI3Kδ lead to a decreased NK cell number and aberrant phenotype. While less well described, patients with loss-of-function mutations in PTEN may have an APDS phenotype that is accompanied by a decreased NK cell number. Studies of short-term KD or OE of PTEN in human NK cells lead to increased and decreased NK cell functions, respectively. P, phosphate; KD, knockdown; OE, overexpression.