Abstract
Abstract Females have stronger immune responses than males. This can be a protective benefit for immune responses to infection and cancer, but also a detriment for the development of autoimmune disease. The genetic contributions to sexually dimorphic immunity are not well understood. We have identified the X-linked histone demethylase KDM5C as an important regulator of T cell immunity. KDM5C escapes X inactivation so is expressed more in females than males. KDM5C demethylates H3K4, participating in gene silencing, however also has a role in promoting gene expression. Mice deficient in KDM5C in immune cells have reduced ability to control acute and chronic infection. CD8 and CD4 T cells have reduced expression of T cell effector molecules and increased expression of PD-1. We find that KDM5C promotes optimal T cell responses through epigenetic and metabolic programming. These data implicate KDM5C as an important promoter of T cell immunity and a mechanism underpinning sexual dimorphic immune responses to infection.
Published Version
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