Innate lymphoid cells in tissue homeostasis and diseases

Table 1 Innate lymphoid cell functions across the intestine during homeostasis and inflammatory diseases

ILC subtype	Function	Model	Evidence	Ref.
ILC1	T. gondii infection	Oral infection C57BL/6 mice	Immunity to T. gondii infection is IFNγ-dependent; mice lacking T-bet expression had virtually no IFN-g production in response to T. gondii infection and failed to control parasite replication	[9]
ILC2	N. brasiliensis infection	Balb/c subcutaneous infection	Combined absence of IL-25 and IL-33 signaling led to a defect in worm expulsion, that was rescued by ILC2-adoptive transfer	[34]
ILC3	S. Thiphymurium infection	Fut2-deficient C57BL/6 mice	Fucosylation of intestinal epithelial cells is catalyzed by Fut2; IL-22-derived ILC3s induce the expression of Fut2. Disruption of intestinal fucosylation led to increased susceptibility to infection by S. Typhimurium	[57]
ILC3	C. rodentium infection	Oral infection C57BL/6 mice	Mice lacking IL-22-producing ILC3 cells showed heightened susceptibility to the pathogen	[54,62]
ILC3	C. albicans infection	C57BL/6 and BALB/c mice	IL-22 mediates protection in IL-17RA-deficient mice; an early IL-22-dominated response is then followed by Th1/Treg reactivity	[65]
ILC2	Epithelium repair after intestinal inflammation	C57BL/6 DSS-induced colitis	Number of AREG-expressing ILC2s increases following intestinal inflammation. Disruption of the AREG-EGFR pathway exacerbated disease	[74]
ILC3	Repair of lymphoid tissue	C57BL/6 mice	LCMV infection induces the destruction of secondary lymphoid organs RORγ-deficient WT chimeras had impaired rebuilding of stromal cell compartment after LCMV infection	[70]
ILC3	Regeneration of intestinal epithelium	C57BL/6 mice	Intestinal microbiota represses the ILC3-producing IL-22 through the induction of IL-25 by IECs. RAG-2-deficient mice treated with IL-25 showed significant weight loss in response to DSS treatment	[68]
ILC3	Containment of the gut microbiota	C57BL/6 mice	Depletion of IL22-producing ILC3s resulted in peripheral dissemination of commensal bacteria and systemic inflammation, which was prevented by administration of IL-22	[80]
			Ablation of LTα in RORgt + cells abrogated IgA production in the gut and altered microbiota composition	[81]
ILC1	Crohn’s disease	Human	ILC1 population is increased in the inflamed intestine of people with Crohn’s disease	[29,30]
ILC1	Ulcerative colitis	Anti-CD40 colitis model	IELs from the small intestine of mice treated with anti-CD40 revealed a robust production if IFN-γ by ILC1s. Anti-Nk1.1 treatment reduced inflammatory infiltration and epithelial damage, suggesting that ILC1 can contribute to colitis through IFN-γ secretion	[85]
ILC3	Ulcerative colitis	Anti-CD40 colitis model	ILC3s secrete higher amounts of GM-CSF which in turn recruits pathogenic Ly6C+ inflammatory monocytes, increasing inflammation and tissue damage	[86]
ILC3	Crohn’s disease	Human	Inflamed tissue from patients with CD showed accumulation of IL-23-responive ILCs and increase expression of IL-17	[91]
ILC3	Colorectal cancer	C57BL/6 mice	Absence of IL-23 promotes tumor development accompanied by increased innate immune cell infiltration; tumorigenesis induced by IL23 could not be initiated in RAG2-/-IL-2R-/- double knockout mice; IL-23R expression was identified in gut associated lymphoid tissue	[49]
				[93]

IFN: Interferon; Fut2: Fucosyltransferase 2; AREG: Amphiregulin; LTα: Lymphotoxin α; LCMV: Lymphocytic choriomeningitis virus; GM-CSF: Granulocyte-macrophage colony-stimulating factor; EGFR: Epidermal growth factor receptor; IL: Interleukin; ILC: Innate lymphoid cell.