Development and maturation of natural killer cells

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Highlights

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    How do NK cells diverge from other innate lymphocyte cell fates?

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    Transcription factors key in early NK cell development include Nfil3, Ets family.

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    Transcription factors critical for NK cell maturation include Id2, T-bet, Eomes.

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    Activating cytokines, STATs control NK cell cytotoxicity and IFN-γ production.

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    Apoptosis and autophagy regulate development of memory NK cells.

Natural killer (NK) cells are innate lymphocytes that are critical for host protection against pathogens and cancer due to their ability to rapidly release inflammatory cytokines and kill infected or transformed cells. In the 40 years since their initial discovery, much has been learned about how this important cellular lineage develops and functions. We now know that NK cells are the founding members of an expanded family of lymphocyte known as innate lymphoid cells (ILC). Furthermore, we have recently discovered that NK cells can possess features of adaptive immunity such as antigen specificity and long-lived memory responses. Here we will review our current understanding of the molecular mechanisms driving development of NK cells from the common lymphoid progenitor (CLP) to mature NK cells, and from activated effectors to long-lived memory NK cells.

Introduction

NK cells, like B and T cells, are a lymphocyte lineage derived from the CLP [1], and like B cells, are thought to develop primarily in the bone marrow [2], although other sites of development, such as the liver and thymus, have also been proposed (reviewed in [3]). However, unlike the antigen receptors of B and T cells, NK cell receptors are germ line encoded and do not require gene rearrangement by RAG recombinase [4], though recent work has suggested that RAG plays an unexpected cell-intrinsic role in NK cell development [5••]. NK cells also undergo an ‘education’ process during development where they acquire the ability to recognize lack of self MHC class I, or ‘missing-self’, a feature that facilitates their surveillance of target cells that have down-regulated MHC class I during infection or malignancy [6]. NK cells rely on both cytokines and transcription factors to promote and control their development. Cytokine signaling from interleukin (IL)-15 is critical for the development of NK cells and is required throughout their lifetime [7, 8]. Transcription factors such as Nfil3 and PU.1 are necessary for development of early NK cell progenitors [9, 10, 11, 12], whereas Id2, Tox, and others are important later in development [13, 14, 15]. Eomes and T-bet are among factors that then control the final stages of NK cell maturation [16, 17]. In the periphery, the activation and differentiation of NK cells are regulated by a plethora of transcription factors mediating distinct effector functions. This review will outline current knowledge about the stages of NK cell development and the factors driving each stage.

Section snippets

Stages of NK cell development and differentiation

The CLP is characterized by expression of IL-7Rα (CD127), c-kit (CD117), Sca-1, and Flt-3 (CD135), as well as the lack of common lineage markers such as CD3, CD4, CD8, CD19, Ter119, Gr-1 and NK1.1 (Figure 1) [1]. From the CLP, cells develop into NK cell precursors (NKP), which are defined by expression of the IL-15 receptor β chain (CD122), and lack of common lineage markers, including the NK cell markers NK1.1 and DX5 (CD49b) (Figure 1) [2]. This NKP population has been further refined based

Transcriptional control of early NK cell development

Lineage commitment to either an adaptive or innate lymphocyte cell fate is determined by a complex network of transcription factors (Figure 2). For example, Notch signaling through the ligands Jagged1 and Jagged2 preferentially drives NK cell development from the CLP [28, 29, 30], whereas delta-like ligands (DLL) promote T cell development [31]. Moreover, thymocytes can be diverted into an NK cell-like fate if the Notch1-dependent transcription factor Bcl11b is ablated during T cell development

Transcription factors governing NK cell maturation

In addition to the early role for Id family transcription factors in suppressing the adaptive lymphocyte fate while promoting innate lymphocyte development, these factors are also important later in the development of NK cells. Id2-deficient mice have a cell-intrinsic lack of peripheral NK cells [13] that was found to be due to an arrest at the iNK stage [14], indicating that Id2 is important in the transition from immature to mature NK cell. Both Id2 and Id3 are expressed in NKP, and Id2

Regulation of effector NK cell responses and memory formation

The STAT family of transcription factors contains members that are phosphorylated downstream of pro-inflammatory cytokine receptors and form homo-dimers or hetero-dimers that translocate to the nucleus to induce gene transcription (reviewed in [80]). During viral infection, type I IFNs and downstream STAT1 have been shown to enhance NK cell cytotoxicity (Figure 3) [81, 82], and shield activated NK cells from cell death via an NKG2D-dependent fratricide mechanism [83•]. IL-12 and downstream

Concluding remarks

As is evident by the number of groundbreaking studies discussed in this review, the development of NK cells is a highly dynamic process and new discoveries occur each week. Still, there is so much we do not yet understand. Future work will elucidate the mechanisms regulating the various factors described above, how the factors interact with each other, and how they might be involved in disease processes.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank members of the Sun lab for helpful discussions. In particular we thank Aimee Beaulieu, Clair Geary, and Tim O'Sullivan, who read and commented on this review. We apologize to those whose work we were unable to discuss due to space limitations. TLG is supported by a fellowship from the National Institute of Allergy and Infectious Diseases (F31 AI114019). JCS is supported by the Searle Scholars Program, the Cancer Research Institute, and National Institutes of Health grants AI085034 and

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