Group 2 innate lymphoid cells: cellular interfaces in neural–immune crosstalk

Abstract

Group 2 innate lymphoid cells (ILC2) are tissue-resident innate immune cells that function as critical cellular interfaces bridging the nervous and immune systems. In peripheral barrier tissues, ILC2s express a diverse repertoire of receptors for neurotransmitters and neuropeptides, enabling them to integrate neuronal signals that shape type 2 immune responses in the lung, intestine, and skin. This neuroimmune dialogue operates through bidirectional circuits: while neuronal inputs calibrate ILC2-mediated inflammation and tissue repair, ILC2-derived cytokines and growth factors reciprocally modulate neuronal activity and tissue innervation. Dysregulation of these neuro–ILC2 axes has been implicated in a spectrum of diseases, including allergic asthma, inflammatory bowel disease, and atopic dermatitis. Recent studies have further revealed that ILC2s populate central nervous system (CNS) border compartments, including the meninges and choroid plexus, where they contribute to brain development, aging-associated cognitive decline, neurological recovery after traumatic brain injury (TBI) and stroke, as well as CNS autoimmunity and inflammation. In this review, we summarize recent advances regarding the pivotal role of ILC2s in neural-immune crosstalk, discuss the pathophysiological consequences of neuro–ILC2 axis dysregulation, and highlight emerging therapeutic strategies targeting these cellular interfaces for the treatment of inflammatory, allergic, and neurological diseases.