# Sex Differences in NK Cells Mediated by X-linked UTX

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $652,282

## Abstract

PROJECT SUMMARY/ABSTRACT
Viral infection outcomes are sex-biased, with males generally more susceptible to human cytomegalovirus
(HCMV) and other viral infections compared to females. These differences may reflect sexual dimorphism in
immune cell composition and function. As such, it is surprising that numbers of natural killer (NK) cells, a first
line of defense against HCMV, are increased in males compared to females. Here we show in mouse models
and human samples that while males harbor increased NK cell numbers, they produce less IFN-γ, a critical pro-
inflammatory cytokine for NK-mediated anti-viral responses. This difference is not due to divergent levels of
gonadal hormones, since these differences are still present in gonadectomized mice. Instead, a screen for X
chromosome genes that escape inactivation and demonstrate sexually dimorphic expression in NK cells
identified UTX, an epigenetic regulator that alters transcriptional programs through reorganization of chromatin.
NK cell-specific UTX deletion phenocopies multiple features of male NK cells, which include increased NK
numbers and reduced IFN-γ production. Thus, we hypothesize that NK cell sex differences can be attributed to
differential expression of X-linked UTX, which reorganizes chromatin at loci important in NK cell fitness and
function. In Aim 1, we will define UTX-mediated temporal control of NK cell numbers and determine whether
differences in cellular fitness underlie differences in NK cell homeostasis in males compared to females. In Aim
2, we will delineate UTX’s role in promoting NK cell cytotoxic activity and whether lower UTX levels in male NK
cells also impairs their cytotoxic capacity. In Aim 3, we will delineate molecular mechanisms by which UTX
controls chromatin accessibility and gene expression at loci important for NK cell homeostasis and function.
Knowledge gained from completion of these studies will contribute to our basic understanding of sex differences
in anti-viral responses and NK cells. A deeper understanding of sex differences will benefit human health overall
by revealing new targets for immunotherapy and guiding interventions for optimizing anti-viral immunity.

## Key facts

- **NIH application ID:** 10750843
- **Project number:** 1R01AI174519-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Timothy E O'Sullivan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $652,282
- **Award type:** 1
- **Project period:** 2023-07-07 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10750843

## Citation

> US National Institutes of Health, RePORTER application 10750843, Sex Differences in NK Cells Mediated by X-linked UTX (1R01AI174519-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10750843. Licensed CC0.

---

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