Specialized immune cells bridge the nervous and immune systems

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. 

The review further details organ-specific regulatory circuits. In the lung, ILC2s form neuro–immune modules with pulmonary neuroendocrine cells, integrating mechanical, chemical, and immune signals to coordinate airway defense. In the intestine, the enteric nervous system regulates ILC2s through multiple parallel pathways including NMU-NMU receptor 1 (NMUR1), acetylcholine (ACh)-Chrm4, and adrenomedullin 2 (ADM2) signaling to balance anti-helminth immunity and mucosal homeostasis. In the skin, TRPM8+ sensory neurons activate ILC2s through IL-18, translating cold stimuli into IL-5-mediated thermogenic responses, achieving neuro–immune-metabolic integration. 

The functional territory of ILC2s extends beyond the periphery. Recent studies have revealed that ILC2s reside in CNS border compartments including the meninges and choroid plexus, playing multiple roles in brain development, aging, neuroinflammation, and injury repair. During critical developmental windows, meningeal ILC2s secrete IL-13 to directly promote inhibitory synapse maturation, establishing the first causal link between innate immune cells and social behavior neural circuits. In the aging brain, ILC2s accumulate functionally in the choroid plexus and, upon activation, suppress neuroinflammation through IL-5, promoting hippocampal neurogenesis and reversing age-associated cognitive decline. In Alzheimer's disease models, ILC2s show both numerical and functional deficits, with exogenous IL-5 supplementation improving learning and memory. Following stroke, traumatic brain injury, and spinal cord injury, IL-33 recruits ILC2s to injury sites, promoting neurogenesis and tissue repair through amphiregulin-EGFR pathways. 

However, "ILC2s are not uniformly protective," the author highlighted. The team's recent research found that dural ILC2s can activate myelin-reactive T cells through MHC class II-dependent antigen presentation in experimental autoimmune encephalomyelitis, secreting interferon-gamma and IL-17A to exacerbate CNS neuroinflammation and demyelination. This finding reveals the context-dependent nature of ILC2 function-their functional polarity depends on the tissue microenvironment and disease stage-offering new insights for precision intervention in multiple sclerosis and related disorders. 

The therapeutic landscape for targeting the neural-ILC2 axis is rapidly expanding. In the periphery, NMUR1 antagonists, β2-adrenergic agonists, and dopamine analogs show promise in curbing allergic inflammation, while enteric neuron-derived ADM2 has demonstrated therapeutic benefit in inflammatory bowel disease models. In the CNS, ILC2 adoptive transfer and IL-5 intervention have achieved proof-of-concept in models of age-associated cognitive impairment, brain trauma, and stroke. 

Despite this promise, clinical translation faces key challenges. Species differences in neuro-receptor expression profiles between mouse and human ILC2s, the blood-brain barrier limiting CNS delivery, and the heterogeneity and plasticity of ILC2s all require precise spatiotemporal targeting strategies. "Future directions integrating in vivo imaging, spatial transcriptomics, and single-cell multi-omics will map tissue-specific neural-ILC2 circuitry, providing a foundation for individualized intervention," the author prospected. 

In conclusion, as central hubs integrating neural-immune-metabolic networks, ILC2 research is driving deep convergence across immunology, neuroscience, and physiology. From immune defense at peripheral barriers to neural plasticity at CNS borders, from acute injury repair to chronic neurodegenerative diseases, ILC2-mediated neural-immune dialogue provides a unified framework for understanding how the body integrates neural signals with immune responses, opening new therapeutic frontiers for allergic diseases, neuroinflammation, and neurodegeneration.