The X Factor in Immunity: Sex Differences Shaped by the X Chromosome

ABSTRACT There are sex differences with immune responses where females exhibit stronger immune responses compared to males. Both sex hormones and sex chromosome differences between males and females contribute to the observed sex differences with innate and adaptive immune cell composition and function. Here, we present recent findings investigating sex differences with immune cells and responses, highlighting contributions from sex hormones or X‐linked genes. We also review the epigenetic gene regulatory mechanisms that form the inactive X chromosome (Xi), known as X‐Chromosome Inactivation (XCI), the heterochromatic nature of the Xi that allows for selective gene reactivation, and recent work investigating the mechanisms of XCI maintenance in female immune cells. We also highlight some dosage‐sensitive X‐linked genes involved in female‐biased autoimmune disease, discuss sex differences with immune signaling pathways, and sex differences with viral infections and vaccine responses with the ultimate goal to leverage these insights for the development of sex‐specific therapeutic interventions for immune‐related diseases.