Sex differences in NK cells mediated by the X-linked epigenetic regulator UTX

Cheng, M. et al. (BioRxiv) doi: 10.1101/2022.04.21.489076

Keywords

  • Natural Killer Cells

  • X-linked traits

  • Sex differences in immunity

 

Main Findings

Natural killer (NK) cells are key to successful antiviral immune responses. Previous studies have identified influences of sex hormones on NK cells and other immune cells. However, non-hormonal mechanisms underlying differences in immune cell phenotype between XX and XY individuals have remained largely unexplored. Cheng et al. uncover a role for UTX, a histone demethylase enzyme, in driving differences in NK cell frequency and numbers, and functional phenotype, between males and females.

The authors find that UTX, an X-linked gene that escapes X chromosome inactivation and is therefore more highly expressed in females, drives reduced NK cell expansion and higher NK cell IFNγ production in female NK cells compared to males. To demonstrate the role of non-hormonal sex-based differences on NK cells, the authors establish that the increased NK cell numbers and decreased IFNγ production found in male humans is recapitulated in splenocytes from gonadectomized mice. Utilizing an unbiased approach, they identify UTX, an epigenetic regulator, as the most highly differentially expressed X-chromosome inactivation escapee between male and female NK cells from gonadectomized mice. The authors utilize NK cell-targeted knockdown of UTX in female gonadectomized mice to uncover the causal link between lower UTX expression and the increased NK cell number and decreased effector function seen in males. Importantly, they discover differential chromatin accessibility and expression levels of key genes involved in NK cell survival and effector function in UTX knockdown compared to wild type NK cells. Specifically, wild type NK cells had increased chromatin accessibility and expression of Ifng compared to UTX knockdown cells, recapitulating the increased effector potential of human female NK cells. Additionally, UTX knockdown cells had a higher ratio of Bcl-2:Bim proteins, key regulators of apoptosis, indicating that NK cells with reduced UTX expression have improved survival, contributing to the higher NK cell numbers found in males.

To demonstrate the clinical relevance of UTX as a regulator of NK cell phenotype and function in the context of viral infection, the authors infect WT mice and mice with an NK cell-specific deletion of UTX with MCMV, a virus which requires IFNγ production by NK cells for a successful antiviral response. Mice with UTX knockdown NK cells had a greater than 50% reduction in overall survival compared to WT, highlighting the important causal role of UTX expression levels in disease outcome.

Overall, this preprint makes a convincing argument for reduced UTX expression contributing to reduced NK cell anti-viral protection in males and outlines an opportunity for therapeutically modulating NK cell function through UTX expression.

Limitations

  • The main limitation of this study is that all causal relationships are assumed through UTX knockout and differential chromatin accessibility, but the regions of chromatin controlled by UTX are not directly assessed.

  • Additionally, their analysis of NK cell behaviour is primarily limited to frequency/numbers and IFNγ production.

Significance/Novelty

 

Previous studies have examined hormone-driven differences in NK cell phenotype between sexes, but few have looked at non-hormone causal factors that could influence males’ reduced anti-viral immunity. This study identifies UTX as a key regulator of sex-based differences in NK cell function, identifying a potential future target for therapeutic modulation of NK cell anti-viral protection.

Credit

Reviewed by Ashley Reid Cahn as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai, the Kennedy Institute of Rheumatology and the Oxford Centre for Immuno-Oncology  (OXCIO) (University of Oxford, GB) and Karolinska Institute’s Center for Infectious Medicine (CIM) & Center for Molecular Medicine (CMM).