Cell type-specific enhancers regulate IL-22 expression in innate and adaptive lymphoid cells

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Interleukin-22 (IL-22) is vital for epithelial barrier immunity and homeostasis.
• Dysregulated IL-22 contributes to chronic inflammatory conditions like colitis and psoriasis.
• Regulatory mechanisms governing IL-22 expression remain largely uncharacterized.

Purpose of the Study:

• To identify and characterize novel regulatory elements controlling IL-22 gene expression.
• To investigate the differential roles of these elements in various type 3 lymphoid cell subsets.
• To understand the molecular basis for cell-type-specific IL-22 regulation.

Main Methods:

• Bioinformatic analysis to identify conserved non-coding regions.
• CRISPR/Cas9 gene editing to delete putative enhancer regions.
• Reporter assays to measure enhancer activity.
• In vivo studies using mouse models of infection and inflammation.

Main Results:

• Two conserved enhancers, E22-1 and E22-2, were identified and validated.
• Both enhancers are essential for IL-22 production in type 3 lymphoid cells.
• E22-1 regulates IL-22 in both T helper (Th) and innate lymphoid cells (ILCs).
• E22-2 specifically drives IL-22 expression in ILC3s, dependent on Runx3 binding sites.
• These enhancers are critical for gut antimicrobial peptide expression, host defense against Citrobacter rodentium, and IL-22-driven psoriasis development.

Conclusions:

• Distinct cis-regulatory elements control IL-22 expression in different type 3 lymphoid cell subsets.
• E22-2 acts as a specific enhancer for IL-22 in ILC3s, mediated by Runx3.
• These findings reveal novel insights into the regulation of IL-22, impacting our understanding of barrier immunity and inflammatory diseases.