Gene Regulatory Programs of NK Cells Show That NCAM1 (CD56) and KIRs Are Controlled by Genetically Polymorphic Distal Regulatory Elements

ABSTRACT Owing to their immunoprotective properties, natural killer (NK) cells are critical for the innate immune response to pathogens, as well as a new wave of cancer immunotherapy that harnesses natural cytotoxicity. We sought to study the genetic and epigenetic drivers behind human‐specific NK cell receptors, so that we can better understand the underlying cellular function. Here, we present a transcriptomic, proteomic (CITE‐seq), and chromatin (single nuclei ATAC‐seq) profiling of human peripheral NK cell subsets, which was then compared with genomic databases. Through integrative multi‐omics, we demonstrate that CD56 bright versus CD56 dim NK cell subsets have differential distal regulatory element (DRE) landscapes, with fewer accessible DREs in the CD56 dim NK cells. We combine our epigenetic data, deposited Hi‐C, and human genetic data to show mechanisms governing the NCAM1 (encoding CD56) and the killer cell immunoglobulin‐like receptors (KIRs) loci. We identify an NCAM1 DRE that binds STAT3 in most NK cells, while identifying a genetic cohort that has motifs for binding repressive BLIMP1 at the DRE and resulting in less CD56 expression. Together, our findings reveal novel epigenetic and transcriptomic systems for the regulation of NK cell receptors driving NK cell cytotoxicity and diversity.