Group 3 ILCs promote homeostasis and function of the enteric nervous system

The enteric nervous system (ENS) is essential for human health by supporting key gastrointestinal functions such as peristalsis and absorption. Emerging paradigms indicate that neurons also fundamentally influence mucosal immunity and inflammation, in part by acting on tissue-resident lymphocytes, but it remains unknown whether these interactions are reciprocal. Here, we find that lymphoid tissue inducer (LTi)-like group 3 innate lymphoid cells (ILC3s) are genetically poised to interact with the ENS. Among these potential interactions, bone morphogenic protein 2 (BMP2) is abundantly expressed by ILC3s in the healthy human and mouse intestine. Strikingly, experimental deletion of BMP2 in ILC3s, but not macrophages, resulted in reduced overall density of enteric neurons (ENs) in the large intestine and slowed colonic motility. Optimal expression of BMP2 in ILC3s requires RORyt and is enhanced by environmental cytokines signalling through NF-kB. Mechanistically, we find that BMP2 from ILC3s is continuously required to support post-developmental abundance of both excitatory and inhibitory ENs in the gut. Finally, loss of BMP2 in ILC3s leads to a significant reduction in the phosphorylation of SMAD1/5/8 in ENs, indicative of direct signalling. These results demonstrate that ILC3-derived BMP2 critically supports optimal homeostasis and function of the ENS.