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Co-Culture of Murine Small Intestine Epithelial Organoids with Innate Lymphoid Cells
Published on: March 23, 2022
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Setd2 determines distinct properties of intestinal ILC3 subsets to regulate intestinal immunity
Jiali Chang1, Xiaojuan Ji1, Tian Deng2
1CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Cell Reports
|March 16, 2022
Summary
Setd2, a histone modifier, influences innate lymphoid cell subsets (ILC3s) in the gut. Its deletion boosts cytotoxic NKp46+ ILC3s but impairs other ILC3s, impacting intestinal immunity and inflammation.
Area of Science:
- Immunology
- Epigenetics
- Cell Biology
Background:
- Group 3 innate lymphoid cells (ILC3s) are crucial for intestinal immunity and exhibit functional heterogeneity.
- Histone modifications, including methylation, are implicated in regulating immune cell differentiation and function.
Purpose of the Study:
- To investigate the role of Setd2, a histone H3K36 methyltransferase, in the development and function of ILC3 subsets.
- To elucidate how Setd2-mediated epigenetic regulation impacts ILC3 heterogeneity and intestinal immune homeostasis.
Main Methods:
- Utilized a mouse model with Setd2 deletion specifically in ILC3s (Rag1-/-RorcCreSetd2flox/flox).
- Analyzed ILC3 subset populations (NKp46+, NKp46-), their gene expression, and functional capacities.
- Assessed intestinal lymphoid tissue formation, immune cell accumulation, and inflammatory responses.
Main Results:
- Setd2 deletion in ILC3s increased NKp46+ ILC3s with enhanced cytotoxicity and tumor suppression.
- Fewer CCR6+ ILC3s and impaired solitary intestinal lymphoid tissue formation were observed.
- Reduced GM-CSF production by NKp46- ILC3s and decreased CD11b+CD103+ dendritic cell accumulation occurred.
- Setd2 deficiency in NKp46- ILC3s correlated with disturbed Treg homeostasis and intestinal inflammation.
Conclusions:
- Setd2 critically regulates ILC3 subset identity and function through epigenetic mechanisms.
- Setd2's differential impact on ILC3 subsets shapes intestinal immunity and susceptibility to inflammation.
- Targeting Setd2 may offer therapeutic avenues for modulating gut immunity and inflammatory diseases.
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