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  • Developmental relationships between CD bright and

    2020-09-25

    Developmental relationships between CD56bright and CD56dim NK Betamethasone Dipropionate remain unresolved; however, several studies indicate that the former is a precursor of the latter. An NK subset with intermediate features between CD56bright and CD56dim has been identified, corroborating this developmental trajectory (Freud et al., 2017, Yu et al., 2010). However, CD56dim also can convert into CD56bright cells, at least in vitro, in the presence of activating cytokines (Keskin et al., 2007). Several studies also have suggested that these subsets are terminally differentiated and arise from distinct precursors (Berrien-Elliott et al., 2015, Wu et al., 2014). Several nuclear factors have been implicated in the development and function of CD56dim versus CD56bright cells. Patients with mutations in the GATA2 transcription factor (TF) lack CD56bright, but not CD56dim NK cells, supporting a model for their independent development (Mace et al., 2013). Mutations in the MCM4 gene, a DNA helicase associated with replication, specifically compromises the CD56dim population (Gineau et al., 2012). Despite these advances, little information exists on TF-orchestrated regulatory programs for functionally distinct human NK populations, information that will clearly be useful as NK-based cell therapies are optimized. We now report integrative analysis of enhancer and transcriptional landscapes for circulating human NK subsets compared to intra-epithelial innate lymphoid cells 1 (ieILC1), which reside in mucosal microenvironments and produce IFNγ (Fuchs et al., 2013, Simoni et al., 2017). Super-enhancer profiling identified novel genes that functionally specify the CD56dim and CD56bright subsets, including G-coupled protein receptors (G-PCRs), which may modulate human NK function in response to tissue-derived factors. Our analyses established parallels in function and homing potential between self-renewing T memory cells and the CD56bright population, while the molecular programming of CD56dim cells resembles that of effector T memory compartments. Importantly, key TFs governing these phenotypic modules comprise a regulatory scheme employed by both innate and adaptive lymphocytes for localization and effector function, which is evolutionarily conserved from humans to non-human primates and mice.
    Results
    Discussion The collection of IFNγ-producing innate lymphocytes, which are important for controlling microbial infections and transformed cells, display a wide range of functional phenotypes in both humans and mice (Cortez and Colonna, 2016). In mouse, these cells can be grouped phenotypically as helper ILC1s versus cytotoxic NK, which diverge as separate lineages (Constantinides et al., 2015, Klose et al., 2014). In humans, however, functional and lineage relationships between ILC1s and subsets of NK cells, including those found in blood, are not as well defined (Freud et al., 2017, Michel et al., 2016). Given the high priority status of NKs in cell-based therapies for cancer, we require a deeper understanding of the regulatory modules controlling phenotypes for clinical efficacy, such as cytotoxicity, IFNγ production, homing, proliferation, self-renewal, and memory. Our studies approached this problem using integrative -omics analysis of human NK-ieILC1s from distinct microenvironments and functional subsets, including helper and adaptive phenotypes. At both the transcriptional and epigenetic levels, we find that the adaptive subset, CD57+ cytotoxic NK cells, segregated away from a spectrum of more closely related subsets (CD57–, CD56bright, tonsillar NK, and ieILC1s). Beyond this, a small set of signature genes distinguished the five subsets from one another, with a substantial mixing and matching of transcriptional modules to create patchwork expression programs. For example, RUNX2, an osteoblast-restricted gene, was selectively expressed in CD56bright NK cells (Komori, 2010). KLF3, originally thought to be an erythrocyte TF (Crossley et al., 1996, Vu et al., 2011), was selectively expressed in circulating NK cells, but not those found in mucosal tissue. Unexpectedly, circulating CD56dim NK cells shared a small set of genes with ieILC1s residing in a mucosal microenvironment, further underscoring the patchwork nature of NK-ieILC1 expression programs. Although additional studies are required, the CD56dim-ieILC1 shared module may derive from a unique combination of TF expression that includes ZNF683 (HOBIT, ieILC1), PRDM1 (BLIMP1, CD56dim), and IKZF3 (AIOLOS, both).