Acetylcholine production by group 2 innate lymphoid cells promotes mucosal immunity to helminths

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Science Immunology  05 Mar 2021:
Vol. 6, Issue 57, eabd0359
DOI: 10.1126/sciimmunol.abd0359

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Acetylcholine versus helminth infection

Group 2 innate lymphoid cells (ILC2s) play a role in mucosal immune responses during allergy or helminth infection, and different neurotransmitters can regulate ILC2 function. Roberts et al. now show that pulmonary ILC2s can develop a cholinergic phenotype and up-regulate the synthesis and release of acetylcholine (ACh) during infection with the helminth Nippostrongylus brasiliensis. This cholinergic phenotype was associated with ILC2 activation and could also be induced by exposure to Alternaria alternata extracts or the alarmin cytokines IL-33 and IL-25. Genetic disruption of ACh synthesis in ILC2s was associated with greater parasite burdens and reduced lung and gut barrier immunity to N. brasiliensis infection. These results highlight a role for ACh production by ILC2 in protective immune responses against helminth infection.


Innate lymphoid cells (ILCs) are critical mediators of immunological and physiological responses at mucosal barrier sites. Whereas neurotransmitters can stimulate ILCs, the synthesis of small-molecule neurotransmitters by these cells has only recently been appreciated. Group 2 ILCs (ILC2s) are shown here to synthesize and release acetylcholine (ACh) during parasitic nematode infection. The cholinergic phenotype of pulmonary ILC2s was associated with their activation state, could be induced by in vivo exposure to extracts of Alternaria alternata or the alarmin cytokines interleukin-33 (IL-33) and IL-25, and was augmented by IL-2 in vitro. Genetic disruption of ACh synthesis by murine ILC2s resulted in increased parasite burdens, lower numbers of ILC2s, and reduced lung and gut barrier responses to Nippostrongylus brasiliensis infection. These data demonstrate a functional role for ILC2-derived ACh in the expansion of ILC2s for maximal induction of type 2 immunity.

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