Immune microniches shape intestinal T_reg function

Area of Science:

• Immunology
• Gastroenterology
• Systems Biology

Background:

• The intestinal immune system balances tolerance to commensals with pathogen defense.
• Understanding gut immune homeostasis is key to treating inflammatory disorders.
• Spatial organization's role in T regulatory cell function remains unclear.

Purpose of the Study:

• To investigate the spatial and temporal dynamics of microorganism-reactive T regulatory cells in the gut.
• To identify key cellular niches and interactions governing T regulatory cell function during tolerance and inflammation.
• To uncover mechanisms for re-establishing immune tolerance in the gut.

Main Methods:

• In vivo live imaging
• Photo-activation-guided single-cell RNA sequencing
• Spatial transcriptomics
• Analysis of T cell responses to Helicobacter hepaticus

Main Results:

• The lamina propria, not lymphoid aggregates, is the critical niche for effector T regulatory cell function.
• Inflammation disrupts compartmentalization and alters dendritic cell populations.
• A tolerogenic interaction between CD206+ macrophages and effector T regulatory cells was identified in the lamina propria.

Conclusions:

• Spatial compartmentalization in the lamina propria is a key mechanism for maintaining intestinal immune tolerance.
• Disruption of these spatial niches contributes to inflammatory conditions.
• Understanding these interactions can inform the development of novel tolerance-inducing therapies.