ILC3s mediate intestinal immune-epithelial interactions via TGF-β1 activation

Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract. It is characterised by epithelial and immunological dysfunctions, including alterations in populations of Innate Lymphoid Cells (ILCs), including tissue-resident RORγt-expressing Group 3 ILCs (ILC3s). ILC3s contribute to the maintenance of intestinal homeostasis by closely interacting with both the epithelium and adaptive immune cells. Here, we reveal that murine and human ILC3s modulate these interactions through Transforming Growth Factor-Beta 1 (TGF-β1), a pleiotropic cytokine secreted in an inactive form. We show that ILC3s synthesise and activate latent TGF-β1 through mechanical and proteolytic pathways. ILC3s aid the induction of FoxP3⁺ regulatory T cells via TGF-β1 and promote a regenerative transcriptional signature in intestinal epithelial cells. The downstream impact of ILC3-derived TGF-β1 is conserved between mouse and humans, but the TGF-β1 activators expressed by ILC3 differ between the species. In IBD, where ILC3s are reduced in the inflamed intestinal regions, TGF-β1-production and activation machinery remains intact in ILC3s, suggesting this pathway is functional in disease and could be targeted to enhance intestinal homeostasis through promotion of epithelial regeneration and induction of regulatory T cells.