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

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.