Document Type

Article

Publication Date

2-4-2026

Comments

This article is the author's final published version in European Journal of Immunology, Volume 56, Issue 2, February 2026, Article number e70142.

The published version is available at https://doi.org/10.1002/eji.70142. Copyright © 2026 The Author(s).

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. © 2026 The Author(s). European Journal of Immunology published by Wiley-VCH GmbH.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

41636199

Language

English

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