TY - JOUR TI - The ChAT-acetylcholine pathway promotes group 2 innate lymphoid cell responses and anti-helminth immunity AU - Chu, Coco AU - Parkhurst, Christopher N. AU - Zhang, Wen AU - Zhou, Lei AU - Yano, Hiroshi AU - Arifuzzaman, Mohammad AU - Artis, David T2 - Science Immunology AB - Cholinergic ILC2s support helminth clearance The activity of group 2 innate lymphoid cells (ILC2s) is modulated by the action of neuropeptides and small-molecule neurotransmitters. To investigate whether ILC2s are a nonneuronal source of the neurotransmitter acetylcholine (ACh) that could influence potential neuro-immune cross-talk, Chu et al. used a green fluorescent protein (GFP) reporter mouse to analyze ILC2 expression of the ACh-synthesizing enzyme choline acetyltransferase (ChAT) following infection with helminth parasites or exposure to allergens or proinflammatory cytokines. ILC2 expression of the ChAT-GFP reporter was strongly induced in vivo after helminth infection and after exposure to Alternaria or injection of the cytokines IL-33 and IL-25. ACh stimulation of ILC2s increased their production of type 2 cytokines and enhanced helminth expulsion from the small intestine. The cholinergic potential of ILC2s revealed in this study provides further evidence of the complex interplay between the nervous system and innate lymphocytes. Group 2 innate lymphoid cells (ILC2s) reside in multiple tissues, including lymphoid organs and barrier surfaces, and secrete type 2 cytokines including interleukin-5 (IL-5), IL-9, and IL-13. These cells participate in multiple physiological processes including allergic inflammation, tissue repair, metabolic homeostasis, and host defense against helminth infections. Recent studies indicate that neurotransmitters and neuropeptides can play an important role in regulating ILC2 responses; however, the mechanisms that underlie these processes in vivo remain incompletely defined. Here, we identify that activated ILC2s up-regulate choline acetyltransferase (ChAT)—the enzyme responsible for the biosynthesis of acetylcholine (ACh)—after infection with the helminth parasite Nippostrongylus brasiliensis or treatment with alarmins or cytokines including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). ILC2s also express acetylcholine receptors (AChRs), and ACh administration promotes ILC2 cytokine production and elicits expulsion of helminth infection. In accordance with this, ChAT deficiency in ILC2s leads to defective ILC2 responses and impaired immunity against helminth infection. Together, these results reveal a previously unrecognized role of the ChAT-ACh pathway in promoting type 2 innate immunity to helminth infection. Activated ILC2s use the ChAT-acetylcholine pathway to enhance their cytokine production and promote helminth expulsion. Activated ILC2s use the ChAT-acetylcholine pathway to enhance their cytokine production and promote helminth expulsion. DA - 2021/03/05/ PY - 2021 DO - 10.1126/sciimmunol.abe3218 DP - immunology.sciencemag.org VL - 6 IS - 57 LA - en SN - 2470-9468 UR - https://immunology.sciencemag.org/content/6/57/eabe3218 Y2 - 2021/03/08/20:37:57 ER -