p300-Dependent Modulation in Regulatory T Cells Plays a Crucial Role in Allergic Asthma.

RATIONALE Asthma is a chronic inflammatory airway disease, affected by epigenetic modifications. E1A binding protein p300 (p300) is a pivotal histone acetyltransferase that regulates the transcription of diverse genes. OBJECTIVES We investigated the role of p300 in regulating immune responses during allergic asthma. METHODS An allergen-induced asthma model was established in mice with systemic p300 deletion and regulatory T cell (Treg)-specific p300 deletion. Histone acetyltransferase activity and p300 expression were evaluated in asthma-induced mice and biopsy samples from patients with asthma. Next, immune responses of T helper 2 cells and Tregs were investigated. Additionally, chromatin immunoprecipitation- and RNA-sequencing were conducted using the sorted Tregs. Functional studies of guanylate binding protein 5 (GBP5) in Tregs were confirmed through in vitro inhibition and overexpression tests. MEASUREMENTS AND MAIN RESULTS Histone acetyltransferase activity and p300 levels were elevated in mice with asthma. p300 expression was also higher in patients with asthma than in control subjects. Mice with systemic p300 deletion had elevated type-2 immune responses and decreased Treg population and functions. Furthermore, p300 deletion reduced the suppression ability and differentiation potential of Tregs. Allergic inflammation was also exacerbated in mice with Treg-specific p300 deletion. Chromatin immunoprecipitation- and RNA-sequencing revealed GBP5 as a primary target gene of p300 in Tregs. GBP5 overexpression ameliorated the reduction in Treg proliferation caused by p300 depletion. CONCLUSIONS p300 plays a protective role in allergic asthma by enhancing Treg function, partly through GBP5-mediated regulation, thereby suppressing Th2-driven airway inflammation.