A collaborative team led by Professor Jie Zhou at Tianjin Medical University School of Basic Medicine and Professor Qiang Liu at Tianjin Medical University General Hospital published a comprehensive review in Volume 2 of the journal Immunity & Inflammation on September 8, 2026. The article systematically elucidates the molecular mechanisms, tissue-specific regulatory networks, emerging functions in the central nervous system (CNS), and translational prospects of group 2 innate lymphoid cell (ILC2)-mediated neuro–immune interactions.
The nervous and immune systems were once viewed as two independent defense systems. Over the past decade, this classical understanding has been fundamentally revised: neuropeptides, neurotransmitters, and cytokines have been recognized as shared molecular languages between the two systems, while the discovery of neuro–immune cell units has provided an anatomical stage for their physical dialogue. At the center of this paradigm shift, ILC2s are moving from the periphery to the core.
In peripheral barrier tissues including the lung, intestine, and skin, ILC2s form tight anatomical associations with sensory, autonomic, and enteric nerve fibers. Neural regulation of ILC2s operates not through simple on/off signals but through a delicate balance of activating and inhibitory pathways, described as a neural rheostat model. Cholinergic neurons release neuromedin U (NMU), acetylcholine, and vasoactive intestinal peptide as accelerators to activate ILC2s, driving type 2 cytokine production including interleukin (IL)-5 and IL-13. Conversely, calcitonin gene-related peptide, noradrenaline, and dopamine serve as brakes, suppressing excessive ILC2 activation. This bidirectional regulation provides a mechanistic explanation for how stress, feeding, and circadian rhythms integrate to modulate allergic and anti-infective immunity.
Importantly, this dialogue is bidirectional. ILC2s are not passive recipients of neural signals; their secreted cytokines can act back on neurons, forming positive feedback loops. In the lung, ILC2-derived IL-5 stimulates Nav1.8+ sensory neurons to release more vasoactive intestinal peptide (VIP), further amplifying type 2 immune responses. In the intestine, ILC2-produced IL-13 upregulates NMU expression in dorsal root ganglion neurons, reinforcing neural drive. This bidirectional communication means that effective intervention must target both sides of the neural–immune axis.
