The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens^1,2. Recognizing how the diverse network of local cells establish homeostasis and maintains it in the complex immune environment of the gut is critical to understanding how tolerance can be re-established following dysfunction, such as in inflammatory disorders. Although cell and molecular interactions that control T regulatory (T_reg) cell development and function have been identified^3,4, less is known about the cellular neighbourhoods and spatial compartmentalization that shapes microorganism-reactive T_reg cell function. Here we used in vivo live imaging, photo-activation-guided single-cell RNA sequencing^5-7 and spatial transcriptomics to follow the natural history of T cells that are reactive towards Helicobacter hepaticus through space and time in the settings of tolerance and inflammation. Although antigen stimulation can occur anywhere in the tissue, the lamina propria-but not embedded lymphoid aggregates-is the key microniche that supports effector T_reg (eT_reg) cell function. eT_reg cells are stable once their niche is established; however, unleashing inflammation breaks down compartmentalization, leading to dominance of CD103⁺SIRPα⁺ dendritic cells in the lamina propria. We identify and validate the putative tolerogenic interaction between CD206⁺ macrophages and eT_reg cells in the lamina propria and identify receptor-ligand pairs that are likely to govern the interaction. Our results reveal a spatial mechanism of tolerance in the lamina propria and demonstrate how knowledge of local interactions may contribute to the next generation of tolerance-inducing therapies.

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