The role of ILC3 tissue microenvironments in determining intestinal health and disease (360G-Wellcome-227760_Z_23_Z)

The gastrointestinal tract is central to whole body health with loss of tissue function and barrier integrity implicated in chronic inflammatory disease, cancer, autoimmunity, obesity and neurological disorders. The intestine is continually exposed to challenges from the diet, commensal microbiota or invading pathogens. As a result the gut is also host to a complex network of immune cells that synergise to enforce a state of tolerance and promote tissue health. We propose that a subset of immune cells, known as ILC3, are critical tissue-resident "communication hubs" of immunity that orchestrate the wider immune response, regulate inflammation and ensure local and systemic health. We hypothesise ILC3 co-localize to specific microenvironments and facilitate formation of cellular niches to mediate crosstalk that is required for the maintenance of tissue homeostasis. We will utilize next generation technologies and in vivo models to reveal novel mechanisms of immune crosstalk within tissue niches, and dissect the consequences of ILC3-mediated interactions within intestinal-resident cellular networks and sensing of environmental cues in the context of health, infection and inflammatory disease. Together this programme of research will drive paradigm shifts in our understanding of ILC orchestration of immunity, and it’s role in maintaining both intestinal and whole body health.