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

## TL;DR

This study explores how genetic and epigenetic factors regulate NK cell receptors, revealing new insights into their role in immunity and cancer therapy.

## Contribution

The study identifies novel distal regulatory elements controlling NCAM1 and KIRs in NK cells, revealing genetic polymorphisms affecting receptor expression.

## Key findings

- CD56bright and CD56dim NK cells have distinct distal regulatory element landscapes.
- An NCAM1 DRE binds STAT3 in most NK cells but is repressed by BLIMP1 in some genetic backgrounds.
- The study clarifies cis-regulation mechanisms for KIR receptors and NK cell diversity.

## 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 CD56bright versus CD56dim NK cell subsets have differential distal regulatory element (DRE) landscapes, with fewer accessible DREs in the CD56dim 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.

A deeper understanding of the natural killer cell gene expression regulation driving NK cell maturation and cytotoxicity could provide critical insights into optimizing NK therapies. Our findings reveal novel enhancers governing NK cell genes for NCAM1/CD56 and cis‐regulation for KIR receptors and clarify existing models of NK cell cis‐accessibility regulation.