2. Academic Validation
  3. The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences

The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences

  • Nat Immunol. 2023 Mar 16. doi: 10.1038/s41590-023-01463-8.
Mandy I Cheng 1 2,  Joey H Li 1 2,  Luke Riggan 1 2 3,  Bryan Chen 1,  Rana Yakhshi Tafti 1 2,  Scott Chin 1,  Feiyang Ma 3 4,  Matteo Pellegrini 3 4,  Haley Hrncir 5,  Arthur P Arnold 5,  Timothy E O'Sullivan 6 7,  Maureen A Su 8 9 10
Affiliations

Affiliations

  • 1 Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • 2 Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA.
  • 3 Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
  • 4 Institute for Genomics and Proteomics, University of California Los Angeles, Los Angeles, CA, USA.
  • 5 Department of Integrative Biology & Physiology, Laboratory of Neuroendocrinology of the Brain Research Institute, University of California Los Angeles, Los Angeles, CA, USA.
  • 6 Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. [email protected].
  • 7 Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. [email protected].
  • 8 Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. [email protected].
  • 9 Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. [email protected].
  • 10 Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. [email protected].
PMID: 36928413 DOI: 10.1038/s41590-023-01463-8
Abstract

Viral Infection outcomes are sex biased, with males generally more susceptible than females. Paradoxically, the numbers of Antiviral natural killer (NK) cells are increased in males. We demonstrate that while numbers of NK cells are increased in male mice, they display decreased effector function compared to females in mice and humans. These differences were not solely dependent on gonadal Hormones, because they persisted in gonadectomized mice. Kdm6a (which encodes the protein UTX), an epigenetic regulator that escapes X inactivation, was lower in male NK cells, while NK cell-intrinsic UTX deficiency in female mice increased NK cell numbers and reduced effector responses. Furthermore, mice with NK cell-intrinsic UTX deficiency showed increased lethality to mouse cytomegalovirus. Integrative multi-omics analysis revealed a critical role for UTX in regulating chromatin accessibility and gene expression critical for NK cell homeostasis and effector function. Collectively, these data implicate UTX as a critical molecular determinant of sex differences in NK cells.

Figures
Products