Chapter Eight - Human natural killer cell development

Abstract

The development of natural killer (NK) cells in humans can be characterized into five distinct stages according to cell surface expression as pro-NK, pre-NK, immature iNK, CD56bright NK, and CD56dim NK. The location of human NK cell development appears to be multi-centred as NK cells are derived from hematopoietic stem cells in the bone marrow, which travel in the blood to secondary lymphoid tissue where maturation likely occurs and functional responsiveness to the environment begins. The progression in NK cell development involves distinct changes in cell surface phenotype as well as cell function. Congenital defects in the development of T cells and B cells lead in some instances to profound immune deficiencies. Understanding the developmental defects in adaptive immunity has led to the subsequent development of innovative, life-saving therapies for those afflicted. Host defence against invading pathogens and malignant transformation requires a “first line” that can quickly place the foreign invasion in check while the primary adaptive immune response is being developed. This is where the effector arm of the innate immune system comes into play. Natural killer (NK) cells form part of the hosts' first line of defence against such pathogens with the ability to kill targets or prime the immune system with cytokines such as IFN-γ within minutes of directly encountering a cellular target, such as a virus-infected cell, or receiving an activation signal via the provision of cytokines from dendritic cells within secondary lymphoid tissues (SLT). Genetic disruption studies in the mouse demonstrate that cytokines such as interleukin-15, c-kit ligand (KL) and flt3 ligand (FL) are essential for normal NK cell development and are likely important for changes in stage-specific requisite transcription factor expression.