# Investigation of Epigenetic Dysregulation in Lupus NK Cells

> **NIH NIH R21** · STANFORD UNIVERSITY · 2022 · $196,750

## Abstract

PROJECT SUMMARY
 The overarching goal of this proposal is to systematically characterize an epigenetically distinct natural
killer (NK) cell population with hypoacetylated histones. This NK cell subset is reduced in frequency in systemic
lupus erythematosus (SLE) patients with increased disease activity. We will test the hypothesis that this NK cell
subset, which we term “NKSLE cells”, has a distinct cell surface molecule profile, and is functionally different from
other NK cells in cytolytic capacity and cytokine secretion upon activation. We will further examine if NK cell
functions can be altered by experimental manipulation of histone acetylation. Our data will lay a strong foundation
for future epigenomic studies on specific genes or genomic loci pivotal for lupus pathophysiology. The advent of
single-cell technologies has greatly accelerated our understanding of immune system heterogeneity. Increasing
evidence supports a compelling model in which pathologically important cells in SLE may represent only a small
fraction of the highly complex immune system. This proposal builds upon this innovative concept, and will
leverage cutting-edge technologies to interrogate the epigenetic and proteomic heterogeneity of NK cells, and
their complex relationships. In Aim 1, we will employ highly multiplexed mass cytometry to monitor a broad array
of functionally important NK cell markers, such as activating and inhibitory receptors, cell adhesion molecules,
and those indicative of cytotoxicity activity, and histone acetylation abundance in individual NK cells. We will first
benchmark NK cell heterogeneity in healthy blood donors, with a goal to identify cellular features associated with
global histone acetylation level. Next, we will extend the analysis to SLE patients, whose NK cell compartments
show reduced representation of cells with hypoacetylated histones. This study will reveal the phenotypic and
functional characteristics of NKSLE cells. In Aim 2, we will investigate the functional differences between NK cells
with differential histone acetylation content. Cytotoxicity and proinflammatory cytokine secretion are key
immunological functions mediated by NK cells during a viral infection. Mass cytometry will be utilized to examine
how differential histone acetylation abundance in individual NK cells is correlated with the degree of their immune
response upon activation measured by degranulation markers, and cytokine production. Our analysis will first
focus on NK cells isolated from healthy volunteers, and subsequently extend to those from lupus patients to
better understand the clinical significance of NKSLE cell reduction in lupus. Lastly, as opposed to genetic
mutations that are generally refractory to therapeutic interventions, epigenetic phenomena are largely reversible,
making them attractive targets for developing new drugs. We will investigate the plasticity of NK cell functions
by pharmacologically manipulating histone acetylation. Together,...

## Key facts

- **NIH application ID:** 10363743
- **Project number:** 5R21AI159578-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** PAUL JOSEPH UTZ
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $196,750
- **Award type:** 5
- **Project period:** 2021-03-03 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10363743

## Citation

> US National Institutes of Health, RePORTER application 10363743, Investigation of Epigenetic Dysregulation in Lupus NK Cells (5R21AI159578-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10363743. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*