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.
Highlights
Human Natural killer (NK) Cell Development, Lytic Function, and MigrationHuman NK cells are derived from bone marrow precursors and mature in the peripheral tissues, the secondary lymphoid tissue [1,2,3]
CD56bright are considered less mature than the CD56dim subset, and their lesser frequency within peripheral blood is converse to their predominance in the secondary lymphoid tissue, where they are thought to develop [6]
CD56dim NK cells are cited as having the greatest capacity for lytic function; similar capacity for lytic function can be elicited from CD56bright NK cells with cytokine priming or activation [5, 7,8,9,10]
Summary
Human NK cells are derived from bone marrow precursors and mature in the peripheral tissues, the secondary lymphoid tissue [1,2,3]. These can be illustrative of requirements for NK cell development or function, despite involvement of other immune compartments These primary immunodefici encies that affect NK cells range from severe combined immune deficiency as a result of IL2RG [59] or JAK3 [60] mutation, which defines the requirement for common gamma chain cytokine signaling in human NK cell development, to diseases including STAT1 gain-of-function (GOF) mutations [61] and STAT3 deficiency [62]. In each of these cases, it is important to consider that other affected immune compartments can impact NK cell phenotype and function.
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