IL-4-induced decrease in both the number and CTLA-4 expression of T_reg impairs suppression of Th2 type inflammation...

Area of Science:

• Immunology
• Molecular Biology
• Dermatology

Background:

• Regulatory T cells (Treg) are crucial for immune homeostasis and suppressing Th2 cell responses.
• The molecular mechanisms behind Treg dysfunction in atopic dermatitis (AD) and Th2 inflammation are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms driving quantitative and functional alterations of Treg cells in AD.
• To investigate the role of IL-4 in Treg cell impairment in AD pathogenesis.

Main Methods:

• Utilized flow cytometry, mRNA sequencing, co-culture assays, co-immunoprecipitation, and chromatin immunoprecipitation.
• Employed in vitro studies, an AD mouse model, and patient samples from individuals with AD.

Main Results:

• Treg cell numbers increased in mild/moderate AD but decreased in severe AD, correlating with serum IL-4 levels.
• High IL-4 levels, via the IL-4/pSTAT6 pathway, recruit DNMT1 and HDAC2, inhibiting Foxp3 and CTLA-4 transcription.
• IL-4 impaired Treg-mediated suppression of Th2 differentiation; IL-4Rα blockade restored Treg number and function in AD models and patients.

Conclusions:

• Treg cell numbers correlate with AD severity and serum IL-4 levels.
• Elevated IL-4 epigenetically reduces Treg cell number and CTLA-4 expression in AD.
• Reduced CTLA-4 on Treg cells due to IL-4 impairs the suppression of Th2 cell differentiation, contributing to AD pathology.