Molecular and Cellular Pathways in NK Cell Development

Natural Killer (NK) cells are innate lymphocytes that are members of a larger family of “Innate Lymphoid Cells” (ILCs). Both human and mouse NK cells have been well studied and characterized in terms of their effector cytotoxic function as well as their ability to produce cytokines in response to microbial and cellular stress stimuli. Recent discoveries also indicate that NK cells are capable of immunological memory. These special properties make NK cells central players in the defense against pathogen infection, in tumor immune surveillance, and in regulating immune homeostasis. Indeed NK cell-based therapies are currently being applied in the clinic to treat cancer patients. Despite these well-established concepts, (i) NK cell origin, (ii) their cellular developmental stages, and (iii) their regulatory networks are under intense investigation. For instance, transcription factors Nfil3 and PU.1 are necessary for the development of early NK cell progenitors, while Eomes and T-bet are among the factors that then control the final stages of NK cell maturation. In several hematopoietic malignancies, such as leukemia, or in primary NK cell immune-deficiencies in patients bearing mutations such as MCM4, GATA2, IRF8, NK cell differentiation and activity are impaired. However, the molecular mechanisms underlying these defects in NK cells are not fully understood. Moreover, it remains unclear how NK cell development and function are impacted in various diseases, and to what degree NK cell impairments contribute to disease progression. For instance, it has been demonstrated that in patients with myeloid malignancies, the severity of NK cell impairment is correlated with more advanced cancer stages and this impairment is often more pronounced in NK cells found in the tumor microenvironment compared to those in peripheral blood. Moreover, several reports show that, in these patients, reduced expression of activation receptors on the NK cell surface, triggered by both soluble factors and NK cell-to-tumor cell interaction, leads to the dampening of NK cell functions. The emerging role of NK cells in modern medicine is stimulating a need for better understanding of the molecular and cellular basis of their development in order to fully apply their therapeutic potential, and to develop new therapies against cancer and infections.

In this Research Topic, we welcome the submission of Original Research articles, Reviews, and Opinion articles that highlight recent advances in NK cell research, both in humans and in animal models. The topics may range from basic research to clinical applications, with the goal of providing insight into new viewpoints on NK cell lymphopoiesis in both health and disease.