Human NK Cell Development: One Road or Many?

Abstract

CD3^-CD56⁺ NK cells develop from CD34⁺ hematopoietic progenitors (HPCs) in vivo, and this process can be recapitulated in vitro. The prevailing model is that human NK cell development occurs along a continuum whereby common lymphocyte progenitors (CLPs) gradually downregulate CD34 and upregulate CD56. Acquisition of CD94 marks commitment to the CD56^bright stage, and CD56^bright NK cells subsequently differentiate into CD56^dim NK cells that upregulate CD16 and killer immunoglobulin-like receptors (KIR). Support for this linear model comes from analyses of cell populations in secondary lymphoid tissues and in vitro studies of NK cell development from HPCs. However, several lines of evidence challenge this linear model and suggest a more branched model whereby different precursor populations may independently develop into distinct subsets of mature NK cells. A more definitive understanding of human NK cell development is needed to inform in vitro differentiation strategies designed to generate NK cells for immunotherapy. In this review, we summarize current evidence supporting the linear and branched models of human NK cell development and the challenges associated with reaching definitive conclusions.

Keywords: NK cell; adaptive; development; differentiation; immune; innate; precursor; progenitor.

Figure 1

Possible linear and branched models of human NK cell development. In the linear model of human NK cell development, hematopoietic stem cells differentiate into lymphoid-primed multipotential progenitors, which then become common lymphoid progenitors. Lineage commitment occurs at the NK precursor stage. These cells then mature first into CD56^bright NK cells and then CD56^dim NK cells. Differentiation into adaptive NK cells could subsequently occur in response to viral infection. In the branched model of human NK cell development, hematopoietic stem cells differentiate into lymphoid-primed multipotent progenitors, which then differentiate toward common lymphoid or myeloid progenitors. Either of these progenitors could give rise to NK cell progenitors. These NK cell progenitors could then differentiate into CD56^bright, CD56^dim, or adaptive NK cells. Dashed arrows represent hypothetical routes of development/differentiation.