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.