Abstract
Abstract Group 3 innate lymphoid cells (ILC3)-mediated production of the cytokine IL-22 is critical for the maintenance of immune homeostasis in the gastrointestinal tract. How this occurs is not well defined. We found that the function of ILC3s was not constant across the day, but instead oscillated between active phases and resting phases. Coordinate responsiveness of ILC3s in the intestine depended on the food-induced expression of the neuropeptide VIP. Intestinal ILC3s expressed high levels of the G protein–coupled receptor VIPR2 and activation by VIP markedly enhanced the production of IL-22 and the barrier function of the epithelium. Conversely, deficiency in signalling through VIPR2 led to impaired production of IL-22 by ILC3s and increased susceptibility to inflammation-induced gut injury. Thus, intrinsic cellular rhythms acted in synergy with the cyclic patterns of food intake to drive the production of IL-22 and synchronize protection of the intestinal epithelium through a VIP–VIPR2 pathway in ILC3s.
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