Experiments reveal Xist deficiency impairs T cell activation and cytokine production, suggesting implications for autoimmunity.
Description Profound sexual dimorphism has been observed in the immune response. While sex hormones and sex chromosomes are known to contribute to sex bias in immunity, additional sex-specific factors, such as expression of Xist, have not been thoroughly evaluated. Xist is an X-linked long non-coding RNA (lncRNA) expressed exclusively in females. Xist regulates X-linked gene expression in females by facilitating X chromosome inactivation (XCI) during early development. Recent studies reveal Xist modulates immune cell effector function. Notably, these studies are limited to B cells and innate cells. Thus, the role of Xist in T cells is not known. We hypothesize that Xist-driven chromatin accessibility and gene expression changes modulate T cell effector function. To explore this hypothesis we generated mice with a T cell-specific homozygous Xist deletion (CD4-Cre Xist fl/fl). Our studies reveal Xist-deficient CD4+ T cells are defective in proliferation and pro-inflammatory cytokine production following in vitro and in vivo T cell receptor (TCR) stimulation compared to wildtype CD4+ T cells, suggesting Xist plays a critical role in supporting T cell activation. In future studies we will explore the (1) mechanism by which Xist alters T cell effector function and (2) possibility that Xist-driven immunophenotypic changes in T cells contribute to sex bias in autoimmunity.
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Wilkinson et al. (2025) studied this question.
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