KDM5A : A Master Epigenetic Regulator of Th2 Immunity and Allergic Disease Pathogenesis

ABSTRACT Interleukin‐4 (IL‐4) drives Th2 polarisation and allergic inflammation, yet the epigenetic mechanisms regulating Il4 transcription in CD4 + T cells remain unclear. While STAT6 and GATA3 are canonical transcriptional regulators, lysine‐specific demethylase 5A (KDM5A), an H3K4‐specific demethylase, has not been linked to Th2 immunity. Here, we investigate KDM5A's role in IL‐4 production and allergic airway disease (AA). Using DO11.10 TCR‐transgenic mice and CD4 + T cell‐specific Kdm5a‐knockout models, we assessed KDM5A's role in IL‐4 transcription. Chromatin immunoprecipitation (ChIP)‐qPCR evaluated H3K4 demethylation at the Il4 promoter. Cross‐ELISA quantified IL‐4 secretion, and ubiquitination assays analysed KDM5A stability. Lactobacilli‐derived DNA (LgDNA) was administered to disrupt the USP7‐KDM5A axis in AA models. The results showed that KDM5A deficiency abolished TCR activation‐induced IL‐4 production, impairing Th2 polarisation. Mechanistically, KDM5A maintained H3K4 hypomethylation at the Il4 promoter, facilitating STAT6/GATA3 recruitment. TCR signalling enhanced KDM5A promoter occupancy via USP7‐mediated deubiquitination. USP7 stabilisation of KDM5A elevated H3K4 demethylation and IL‐4 transcription, driving AA pathogenesis. LgDNA suppressed USP7 activity, reducing KDM5A promoter binding by 65% and airway inflammation by 72%. In summary, KDM5A acts as an epigenetic rheostat of Th2 immunity, where USP7‐dependent stabilisation licenses STAT6/GATA3 access to the Il4 promoter during TCR activation. Targeting the USP7‐KDM5A axis with LgDNA selectively suppresses pathogenic Th2 responses while preserving physiological IL‐4 functions. Our findings define a novel epigenetic mechanism for allergic disease and establish microbiome‐derived LgDNA as a precision therapeutic strategy.