Transcriptional control of natural killer cell differentiation

Abstract

Summary Natural killer (NK) cells are highly specialized cytotoxic lymphocytes that provide protection against pathogens and malignant cells. They develop from common lymphoid progenitors via a multi‐stage lineage commitment and differentiation process that gives rise to mature NK cells with potent cytotoxic functionality. Although generally considered cells of the innate immune system, recent studies have demonstrated that NK cells have the capacity to mount immune responses with features of adaptive immunity, including robust antigen‐specific clonal‐like expansion and the generation of long‐lived memory cells that mediate enhanced recall responses. Here, we discuss specific transcription factors that have been shown to commonly and uniquely regulate NK cell development and effector and memory responses in experimental mouse models.

Natural killer cell transcriptional control, subsets, receptors and effector function

“…A tantalizing aspect of recent NK cell studies has been the delineation, in mouse and man, of features that reiterate aspects of adaptive immunity: large, antigen-specific expansions of memory cells displaying enhanced functionality. Brillantes and Beaulieu have offered a detailed synthesis of TF control of NK memory function, 8 based especially on work from their laboratory and others using the murine cytomegalovirus model. These studies highlight the roles of TFs such as Runx1 and Runx3 in memory cell development and the overlap between the transcriptional strategies of memory CD8 and NK cell compartments.…”

“…These many thousands of NK cell subsets share a common origin in the common lymphoid progenitor cells of the bone marrow, then differentiating into CD27 + CD244 + pre‐NK cell precursors. Research of the past few years, often looking at NK cell subsets and functional integrity in knockout mouse strains lacking specific transcription factors (TF) has allowed some of the rules to be established for the key transcriptional determinants of NK cell subsets and functions . Although there is a high degree of confidence as to the hallmark TFs that define the transcriptional programmes of polarized T‐cell subsets, we lack the equivalent understanding of NK cell programmes.…”

“…Research of the past few years, often looking at NK cell subsets and functional integrity in knockout mouse strains lacking specific transcription factors (TF) has allowed some of the rules to be established for the key transcriptional determinants of NK cell subsets and functions. 8 Although there is a high degree of confidence as to the hallmark TFs that define the transcriptional programmes of polarized T-cell subsets, we lack the equivalent understanding of NK cell programmes. Among the TFs regulating NK cell development are a number of E26 transformation-specific (ETS) family members.…”

Memory and Memory-Like NK Cell Responses to Microbial Pathogens

“…Since the initial description of MCMV-specific NK cell memory over a decade ago, our understanding of the molecular pathways that shape this response has advanced significantly. These advances, which have been comprehensively summarized in several recent reviews (Rapp et al, 2018;Brillantes and Beaulieu, 2019), include findings of positive regulators of memory cell formation, such as IL-12, the costimulatory molecule DNAM1, the transcription factors STAT4, T-bet, Eomes, Runx1, and CBF-β, the microRNA miR-155, and the pro-mitophagy proteins BNIP3/BNIP3L, as well as negative regulators such as the pro-apoptotic molecule, Bim. Effector-to-memory NK cell differentiation is accompanied by transcriptional and epigenetic alterations, such as increased abundance of Ly6c1 (encoding Ly6C) and Gzmb1 (encoding Granzyme B) transcripts and enhanced chromatin accessibility at the Prf1 (encoding Perforin-1) locus, which support the distinct phenotype and functions of memory NK cells (Bezman et al, 2012;Lau et al, 2018).…”

Transcription factor Zhx2 restricts NK cell maturation and suppresses their antitumor immunity

“…NK cell development and functional maturation are triggered by plenty of extracellular signals (i.e., cytokines), among which IL-15 is critical for both NK cell lineage commitment and terminal maturation ( Huntington et al, 2007a ). In addition, NK cell development is dictated by a series of transcription factors (TFs) that promote the expression of genes coding for effector molecules and surface markers of maturation ( Brillantes and Beaulieu, 2019 ). For instance, Id2 ( Constantinides et al, 2014 ; Delconte et al, 2016 ), STAT5 ( Marçais et al, 2014 ; Vargas-Hernández et al, 2020 ), Tox ( Vong et al, 2014 ), Ets1 ( Barton et al, 1998 ; Taveirne et al, 2020 ), and Nfil3 ( Seillet et al, 2014 ) regulate early stages of NK development, whereas concerted actions of T-bet and Zeb2 determine terminal NK cell maturation and survival ( Gordon et al, 2012 ; van Helden et al, 2015 ).…”