Tissue signals imprint Aiolos expression in ILC2s to modulate type 2 immunity

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Group 2 innate lymphoid cells (ILC2s) exhibit tissue-specific characteristics crucial for regional immune responses.
• The molecular mechanisms governing tissue adaptation in ILC2s are not fully understood.

Purpose of the Study:

• To investigate the molecular and epigenetic mechanisms underlying tissue-specific ILC2 heterogeneity.
• To identify key regulators of ILC2 adaptation to different tissue microenvironments.

Main Methods:

• Transcriptome and epigenetic profiling of ILC2s from five distinct tissues.
• Analysis of transcription factor binding and chromatin accessibility.
• Investigated the role of Aiolos and Aryl hydrocarbon receptor (Ahr) in ILC2 function.

Main Results:

• Tissue microenvironment significantly shapes ILC2 identity, with intestine inducing Aiolos+ ILC2s and lung/pancreas enhancing Galectin-1+ ILC2s.
• Interleukin-33 (IL-33) induces Aiolos expression in non-intestinal ILC2s, promoting eosinophil recruitment and proliferation.
• Aryl hydrocarbon receptor (Ahr) binds to the Ikzf3 locus, enhancing chromatin accessibility and H3K27ac, thereby sustaining Aiolos expression and preventing ILC2 exhaustion.

Conclusions:

• Aiolos is a key mediator of ILC2 tissue adaptation and function, particularly in the gut.
• Ahr plays a critical role in maintaining ILC2 identity and function by regulating Aiolos expression.
• Aiolos represents a potential therapeutic target for type 2 inflammatory diseases.