Our approach including the characterization of histone modif
Our approach, including the characterization of histone modifications in scarce NK subsets, allowed us to identify super-enhancers, which associate with genes endowing a given cell type with its unique identity (Hnisz et al., 2013). Especially intriguing were SEs with distinct activities in NK subsets, such as those proximal to a substantial set of G-PCRs. Given the role of G-PCRs in transmitting microenvironmental cues, the distinctive set of receptors may govern migration of circulating NK cells to different tissues, expression of cytokines, cytotoxic responses, or CD56bright to CD56dim differentiation. Indeed, the cholesterol metabolite 7α,25-dhc, which is produced by virally infected cells (Blanc et al., 2013, Cyster et al., 2014), attenuated IFNγ expression by CD56bright NK cells, presumably through their high levels of GPR183 expression. Consistent with IFNγ inhibition, GPR183 signals through Gαi to inhibit cAMP production (Rosenkilde et al., 2006). Additionally, an NK-restricted SE coats the NMUR1 gene, suggesting that its continued expression may be important for CD56bright and CD56dim NK functions, perhaps by enabling communication with the peripheral nervous system (Veiga-Fernandes and Artis, 2018). A number of G-PCRs (e.g., GPR141) and other SE-associated genes emerging from our data remain uncharacterized, especially with regard to their functions in NK cell biology, thus providing a valuable resource for future studies.
Introduction Studies in the past decade have established T follicular helper (Tfh) cells as the major CD4+ T cell subset providing help to B cells and promoting antibody responses (Crotty, 2014, Ma et al., 2012, Ueno et al., 2015). Tfh cells are essential for the formation of germinal centers (GCs), the site for the selection of high-affinity 520 3 and for the development of B cell memory (MacLennan, 1994, Vinuesa and Cyster, 2011). Tfh cells and their precursors are equipped with multiple features required for B cell help (Crotty, 2014, Ma et al., 2012, Ueno et al., 2015). Interleukin (IL) 21 secreted by Tfh cells potently promotes the growth, differentiation, and class-switching of B cells. Tfh cells in GCs express high levels of inducible co-stimulator (ICOS), a cell surface co-stimulatory molecule crucial for Tfh cell interactions with B cells. CD40 ligand (CD40L) expressed by Tfh cells provides signals to B cells through CD40 for their differentiation and class-switching. Tfh cell differentiation requires the expression of the transcription repressor B cell lymphoma 6 (Bcl-6) and, conversely, is suppressed by the transcription repressor B lymphocyte-induced maturation protein 1 (Blimp-1), a Bcl-6 antagonist. Whether naive CD4+ T cells commit to differentiate into the Tfh lineage is largely pre-determined during the first step, in which CD4+ helper T cells are primed by dendritic cells (DCs) (Vinuesa and Cyster, 2011). Upon interactions with antigen-presenting DCs, a fraction of CD4+ T cells upregulate the expression of chemokine receptor CXCR5 while downregulating CCR7 expression, partly through the upregulated expression of the transcription factors (TFs) Bcl-6 and Ascl2 (Baumjohann et al., 2011, Choi et al., 2011, Kerfoot et al., 2011, Kitano et al., 2011, Liu et al., 2012, Liu et al., 2014). Such changes in the chemokine receptor expression promote the migration of activated CD4+ T cells toward B cell follicles and interactions with B cells at the T-B border. Tfh precursors then increase Bcl-6 expression and eventually differentiate into mature Tfh cells (Vinuesa and Cyster, 2011). In humans, IL-12 secreted by DCs plays an important role during the first differentiation step. Among DC-derived cytokines, IL-12 is the most efficient at inducing human naive CD4+ T cells to express Tfh molecules, including CXCR5, ICOS, and IL-21, and to upregulate TFs important for Tfh cell differentiation, such as Bcl-6, Batf, and c-Maf (Ma et al., 2009, Schmitt et al., 2009, Schmitt et al., 2013, Schmitt et al., 2014). Children who lack the expression of a functional IL-12 receptor β1 chain display fewer CXCR5+ circulating Tfh (cTfh) cells and memory B cells, indicating that signaling through the IL-12 receptor is important for the development and/or maintenance of human Tfh cells (Schmitt et al., 2013). However, IL-12 signals also drive the differentiation program toward the T helper 1 (Th1) cell through the upregulation of the TF T-bet (Szabo et al., 2000). T-bet collaborates with STAT4 activated by IL-12 signals for the expression of interferon (IFN)-γ (Thieu et al., 2008). The produced IFN-γ further provides a positive feedback loop by enhancing T-bet expression through STAT1 activation (Afkarian et al., 2002, Ylikoski et al., 2005).