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

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. Cheng et al. demonstrate that an extra copy of the X-linked epigenetic regulator UTX in females increases natural killer (NK) cell effector function. As NK cells are critical for antiviral immunity, this may explain decreased severity of viral infections in females compared to males.

Automated summary

The outcomes of viral infections are influenced by sex, with males being more susceptible. Surprisingly, males have increased numbers of antiviral natural killer (NK) cells. However, these NK cells in males display decreased effector function compared to females in both mice and humans. The differences are not solely dependent on gonadal hormones and are associated with lower levels of UTX, an epigenetic regulator, in male NK cells. On the other hand, NK cell-intrinsic UTX deficiency in female mice increases NK cell numbers and reduces effector responses, leading to increased lethality to mouse cytomegalovirus.