(A) In Crohn’s disease (CD), ILC1s accumulate in the intestine, while NCR^– ILC3s are reduced. Myeloid cells, including DCs, produce IL-12, stimulating ILC1s to produce IFN-γ and TNF-α. IL-12 also induces transdifferentiation of NCR^– and NCR⁺ ILC3s into ILC1s. IL-23 promotes differentiation of ILC1s into IL-22–producing NCR⁺ ILC3s. Regulatory ILCs (ILCregs) downregulate ILC1s and ILC3s via IL-10 secretion to suppress production of cytokines other than IL-22. ILCregs also produce TGF-β, which promotes their own expansion and survival. Thalidomide and lenalidomide modulate ILC transdifferentiation by selectively degrading Aiolos (ILC1 specific) and Ikaros (ILC nonspecific), increasing ILC3-associated Helios. Sphingosine-1 phosphate receptor 1 (S1PR1) antagonists downregulate ILC3 NCR expression. TNF-α inhibitors directly block TNF-α produced by ILC1s. Ustekinumab and JAK inhibitors target IL-12 and IL-23, while IL-23–specific mAbs target IL-23 and an anti–IL-22 Fc mAb targets IL-22. An anti-NKG2D mAb might modulate ILC1s and NCR⁺ ILC3s, which express NKG2D in mice. (B) In healthy intestine, ILC3s reside largely within lymphoid aggregate cryptopatches (CPs). Early in inflammation (left), IL-23 secretion by myeloid cells is GM-CSF dependent, and GM-CSF production by ILC3s is sustained by IL-23. Later in inflammation (right), GM-CSF recruits additional myeloid cells and mobilizes ILC3s from CPs into adjacent intestinal mucosa. In response to IL-23, ILC3s produce IL-17 and IFN-γ, promoting intestinal inflammation. IL-23 can be blocked by anti–IL-23 mAbs, ustekinumab, and JAK inhibitors. α4β7 Integrin blockade with vedolizumab might inhibit ILC migration from CPs into intestinal mucosa. A FimH antagonist reduces bacterial adherence to the gut, decreasing innate immune activation and improving intestinal permeability. S1PR1 antagonists prevent ILC1/3 maturation and migration and modify ILC functions. Illustrated by Rachel Davidowitz.