Epigenetic regulation of NK cell differentiation and effector functions

Abstract

Upon maturation, natural killer (NK) cells acquire effector functions and regulatory receptors. New insights suggest a considerable functional heterogeneity and dynamic regulation of receptor expression in mature human NK cell subsets based on different developmental axes. Such processes include acquisition of lytic granules as well as regulation of cytokine production in response to exogenous cytokine stimulation or target cell interactions. One axis is regulated by expression of inhibitory receptors for self-MHC class I molecules, whereas other axes are less well defined but likely are driven by different activating receptor engagements or cytokines. Moreover, the recent identification of long-lived NK cell subsets in mice that are able to expand and respond rapidly following a secondary viral challenge suggest previously unappreciated plasticity in the programming of NK cell differentiation. Here, we review advances in our understanding of mature NK cell development and plasticity with regards to regulation of cellular function. Furthermore, we highlight some of the major questions that remain pertaining to the epigenetic changes that underlie the differentiation and functional specialization of NK cells and the regulation of their responses.

Keywords: NK cell; development; epigenetics; memory; transcription factors.

Figure 1

Checkpoints in NK cell development. As NK cells develop, they transit through the body and advance through checkpoints that are controlled by DNA-binding factors. Throughout this process, the expression of developmental markers, cytokine receptors, natural cytotoxicity receptors, and functional competencies are all dynamically regulated resulting in considerable heterogeneity within the NK cell population. Protein expression data are modified from (Freud et al., ; Freud and Caligiuri, 2006) and for “memory” NK cells extrapolated from (Sun et al., ; Hwang et al., 2012).

Figure 2

Transcriptional and epigenetic regulation of key effector molecules. Proposed models for the regulation of perforin, granzyme B, IFN-γ, and TNF-α expression at the transcriptional level through transcription factor binding and changes in the chromatin state.

Figure 3

Proposed models for the generation of “memory” NK cells during a viral infection vs. cytokine priming. (A) The generation of “memory” NK cells during a viral infection likely happens within the context of NK cell education, where an “educated” NK cell expands during a viral infection and exhibits rapid cytotoxicity and inflammatory cytokine production upon a secondary challenge. (B) The generation of “memory” NK cells as a result of cytokine stimulation may result in epigenetic priming of the IFNG locus and/or accumulation of IFN-γ transcripts in the nucleus. This process may be fundamentally different from the generation of “memory” NK cells during a viral infection.