Bone marrow-derived natural killer (NK) cells constitute the major subset of cytotoxic lymphocytes in peripheral blood. They provide innate defense against intracellular infection or malignancy and contribute to immune homeostasis. Large numbers of NK cells are also present in tissues, including the liver and uterus, where they can mediate immunosurveillance but also play important roles in tissue remodeling and vascularization. Here, we review the pathways involved in NK cell lineage commitment and differentiation, discussing relationships to other lymphocyte populations and highlighting genetic determinants. Characterizing NK cells from distinct tissues and during infections have revealed subset specializations, reflecting inherent cellular plasticity. In this context, we discuss how different environmental and inflammatory stimuli may shape NK cells. Particular emphasis is placed on genes identified as being critical for NK cell development, differentiation, and function from studies of model organisms or associations with disease. Such studies are also revealing important cellular redundancies. Here, we provide a view of the genetic framework constraining NK cell development and function, pinpointing molecules required for these processes but also underscoring plasticity and redundancy that may underlie robust immunological function. With this view, built in redundancy may highlight the importance of NK cells to immunity.
Bibliographical noteFunding Information:
The authors thank Samuel Chiang, Timothy Holmes, and Heinrich Schlums for comments on the manuscript and wish to apologize to colleagues whose work could not be adequately cited or discussed due to space constraints. This work was supported by the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement n. 311335, Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Cancer Foundation, Swedish Children's Cancer Foundation, Histiocytosis Association, Jeansson's Foundation, the Karolinska Institute Research Foundation, AFA Försäkring, Gunnar Nilsson Cancer Foundation, ALF Clinical Research Award from Lund University Hospital, Hemato-Linne and Stem Therapy Lund University Programmes, and the University of Minnesota T32 Hematology Training Grant.
- Cytokine production
- Natural killer cells
- Primary immunodeficiency
- Single nucleotide polymorphisms
- Transcription factors