Regulation of type 2 immune responses via neuropeptides and neurotransmitters

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Innate lymphoid cells (ILC) are the first line of defense against infections and orchestrate tissue immune status and homeostasis. ILC2s are involved in type 2 immune responses, including helminth infections and chronic allergic reactions. They produce type 2 cytokines (mainly IL-5 and IL-13) in response to a wide range of environmental stimuli, such as alarmins (IL-33, IL-25, TSLP) and neuromodulators (NE, Ach, CGRP, NMU). Each of these signals and their combination uniquely controls ILC2s' activity. Hence, these cells adopt a heterogenic phenotype in different contexts and tissues. The vasoactive intestinal peptide (VIP), an essential regulator of the circadian system, is a neuropeptide that has been proposed as another regulator of ILC2s. VIP release is known to be influenced by feeding, and ILC2s produce IL-5 in a circadian fashion. However, unlike other neurotransmitters, the precise action, location, and physiological relevance of VIP-mediated regulation of ILC2s are still not fully elucidated. Besides, the lack of efficient and specific genetic tools to interfere with VIP signaling in ILC2s and conflicting studies limit our understanding of this potential neuro-immune circuit. Here, we propose to use our new mouse model that allows the generation of Vipr2 conditional knockout in ILC2s, as well as other existing mouse models, to study VIP neurons in vivo (e.g., INTACT, DREADD systems ), together with a combination of classical (e.g., flow cytometry, cytokines assays), and innovative genomics approaches (e.g., single nuclei RNAseq, and spatial RNAseq) to functionally characterize the interplay of VIPergic neurons and ILC2s. We will first determine whether VIP signaling in ILC2s participates in their heterogeneity, cytokine production, and subsequent eosinophil recruitment to tissues. We will further determine whether this neuro-immune circuit is required during the type 2 immune response using respiratory and oral allergy models. Then we will determine whether this circuit drives circadian ILC2 activity, including IL-5 production and subsequent eosinophils' tissue dynamic. We will further evaluate whether circadian intestinal absorption, motility, and villi architecture, influenced by intestinal eosinophils, rely on the VIP-ILC2 axis. Finally, we will dissect VIP neurons' spatial and temporal activity and their proximity to ILC2s in the small intestine both at steady-state and during food allergy. Altogether, this study will help decipher the physiological functions of an additional neuro-immune circuit involving ILC2s and shed light on a yet elusive role of VIP in the circadian regulation of ILC2s' activity and its impact on eosinophil homeostasis and tissue functions in health and disease.