Developmental stages and pathways of NK cell maturation

Hematopoietic stem cells (HSCs) by definition can differentiate into all types of blood cells. The development of multipotent hematopoietic cells into NK cells is a complex process. It is guided by environmental cues and intrinsic responsiveness of precursor cells to external signals. As hematopoietic progenitors progress in differentiation towards NK lineage, two concomitant processes occur: acquisition of NK specific gene expression pattern and gradual loss of the ability to express genes characteristic for other lineages. Transcription factors play a critical role in guiding lineage determination. There are several factors and events that promote HSC differentiation into the natural killer (NK) cell lineage. These include soluble factors, with a prominent role for interleukin 15, as well as contact- or gradient-dependent signals, such as Gas6/Tyro family of ligands and factors activating Wnt pathway. A complete understanding of the factors that control NK cell differentiation may allow for manipulation of NK cell reconstitution following hematopoietic cell transplantation and efficient ex vivo generation of NK cells for adoptive immune therapy. Interactions of hematopoietic progenitors with the environment provides growth factors and morphogenic signals that affect lineage fate and guide functional maturation via the triggering of inhibitory and/or activating receptors. The progression from multipotent hematopoietic precursors to mature NK cells can be described on the basis of stages of NK cell development. The development of any hematopoietic lineage can follow heterogenous pathways that lead to a common final point-a mature cell. As precursors traverse an individual developmental pathway, they are exposed to distinct sets of transcription factors, differing in magnitude and time of exposure.