AUTHOR=Cichocki Frank , Grzywacz Bartosz , Miller Jeffrey S. 

TITLE=Human NK Cell Development: One Road or Many?

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02078

DOI=10.3389/fimmu.2019.02078

ISSN=1664-3224

ABSTRACT=<p>CD3<sup>−</sup>CD56<sup>+</sup> NK cells develop from CD34<sup>+</sup> hematopoietic progenitors (HPCs) <italic>in vivo</italic>, and this process can be recapitulated <italic>in vitro</italic>. 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<sup>bright</sup> stage, and CD56<sup>bright</sup> NK cells subsequently differentiate into CD56<sup>dim</sup> 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 <italic>in vitro</italic> 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 <italic>in vitro</italic> 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.</p>