IL-4-induced decrease in both the number and CTLA-4 expression of Treg impairs suppression of Th2 type inflammation in severe atopic dermatitis

Abstract

Background: T_reg plays a pivotal role in the suppression of Th2 cell and the maintenance of immune homeostasis. The precise molecular mechanism underlying the disruption of T_reg suppression of Th2 cell and the promotion of Th2 type inflammation in allergic diseases remains elusive.

Objective: This study aims to investigate the molecular mechanism underlying quantitative and functional changes of T_reg in AD.

Methods: The molecular mechanism was investigated using flow cytometry, mRNA sequencing, co-culture experiments, co-immunoprecipitation, chromatin immunoprecipitation, and bisulfite sequencing in vitro or in AD mice model and patients with AD.

Results: Increased proportion of T_reg was detected in mild and moderate AD. Conversely, characteristic decrease in both the number and CTLA-4 expression of T_reg was relevant to serum IL-4 level in severe AD patients, which was verified under a high concentration of IL-4 treatment in vitro. The underlying mechanism is that IL-4/pSTAT6 pathway recruits DNMT1 and HDAC2 to inhibit transcriptional regulation of Foxp3 and CTLA-4 loci. High level of IL-4 impaired the suppression of T_reg against Th2 cell differentiation mediated by CTLA-4, and blockade of IL-4Rα signaling in T_reg restored T_reg number and suppression of Th2 cell in AD model mice and patients with AD.

Conclusion: The number of T_reg is relevant to stratification of severity and serum IL-4 level in patients with AD. Abnormal high level of IL-4 epigenetically triggers a decrease in both the number and CTLA-4 expression of T_reg. The reduced expression of CTLA-4 on T_reg induced by IL-4 impairs suppression of Th2 cell differentiation.

Keywords: Atopic dermatitis; T-helper type 2 cell; epigenetics; interleukin-4; regulatory T cell.