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

UT(se)X differences during immune responses

“…To identify direct effects of UTX in NK cell function, Cheng et al 5 further interrogated the chromatin binding profile of UTX in NK cells with anti-UTX CUT&TAG sequencing. They determined that, of the 395 genes that were accessible and expressed in a UTX-dependent manner, 191 were also bound by UTX, providing strong evidence that these genes were direct UTX targets.…”

“…Although hormonal differences between men and women have often been implicated in these differences 4 , the underlying molecular basis was unclear. In this issue of Nature Immunology, Cheng et al 5 provided strong evidence that sex chromosome dosage controls the number and activity of natural killer (NK) cells, thus regulating antiviral immune responses in a sex-dependent manner (Fig. 1).…”

“…Paradoxically, men tend to have more NK cells than women, yet are more susceptible to viral infection 6 . However, Cheng et al 5 observed that isolated male NK cells produced lower levels of interferon-γ (IFNγ) than female cells after ex vivo stimulation with pro-inflammatory cytokines, in both humans and mice. Male NK cells also showed impaired target cell killing and production of cytotoxic molecules, such as granzyme B and perforin, indicative of overall compromised NK cell responses in male cells.…”

“…Although large portions of one of the two X chromosomes become inactivated in female mammals to correct for gene dosage effects, some genes escape from X chromosome inactivation (XCI), leading to their increased expression 7 . Therefore, Cheng et al 5 postulated that this unequal gene expression pattern may contribute to discrete NK cell responses between sexes. Through gene expression screening, the authors discovered five genes that escape XCI in both mice and humans.…”

“…In an elegant series of experiments, Cheng et al 5 investigated the role of UTX in sex-related immune responses in female mice with heterozygous deletion of the Kdm6a gene (Utx Het ) specifically in NK cells (using the Ncr1 cre mouse model 8 ), which resembled male mice in their levels of UTX. Loss of one Kdm6a allele in female mice led to Female mice with heterozygous deletion of the Kdm6a gene in NK cells showed similar NK cell number and function to male mice, suggesting that UTX is a critical mediator of sex-related immune responses.…”