Spatial-temporal compartmentalization of tolerance in the mammalian gut

The immune system in the gut faces a unique challenge: it must rapidly attack harmful microbes while coexisting with trillions of beneficial bacteria that promote digestion and health. When this balance fails, the immune system can mistakenly attack harmless microbes, leading to pathologies such as IBD. Although scientists have identified rare immune cells that promote tolerance to beneficial bacteria, it remains unclear how such scarce cells orchestrate this process throughout the gut. We propose that the immune system solves this problem by organizing immune responses in space. Specifically, we hypothesize that immune cells called T cells route to different regions within gut-draining lymph nodes based on the strength of the signals they receive. T cells sensing harmless bacteria receive weaker signals and are guided into specialized regions that promote tolerance. Conversely, T cells sensing dangerous pathogens receive stronger signals and remain in inflammatory zones, enabling protective responses. This project will use advanced, high-resolution imaging to map how immune cells interact within lymph nodes under healthy and inflammatory conditions. By uncovering the spatial rules that separate tolerance from inflammation, we aim to understand why immune balance breaks down during IBD and identify new strategies for restoring immune regulation in the gut.