Divija Deshpande

Type 2 immunity has evolved to protect against worms but becomes harmful when activated during allergic inflammation. Group 2 innate lymphoid cells (ILC2s) drive type 2 responses by rapidly secreting IL-5 and IL-13. The alarmins, IL-25, IL-33, and TSLP activate ILC2s and are linked to allergic diseases. However, how alarmins connect to the transcriptional networks driving type 2 effector functions remains elusive. Here, we performed RNA sequencing of ILC2s deficient in IL-25, IL-33, or TSLP pathway and identified the transcription factor Blimp-1 as an IL-33–regulated gene in ILC2s. While Blimp-1 was dispensable for ILC2 development, this transcription factor was required for type 2 cytokine production, driving eosinophilia or promoting worm expulsion. Blimp-1 deficiency resulted in reduced IRF4 expression, while Irf4-deficient ILC2s showed diminished Blimp-1 and IL-33 receptor expression, revealing a reciprocal Blimp-1–IRF4 circuit downstream of the IL-33 receptor. These findings expose the Blimp-1–IRF4 axis as an alarmin-regulated transcriptional network controlling ILC2 effector functions required for type 2 immunity.

Barrier homeostasis relies on a finely tuned interplay between the immune system, epithelial cells and commensal microbiota. Beyond these regulators, the enteric nervous system has recently emerged as a central hub coordinating intestinal immune responses, although its role in epithelial differentiation has remained largely unexplored. Here, we identify a neuroepithelial circuit in which vasoactive intestinal peptide (VIP)-positive enteric neurons act on VIPR1⁺ epithelial stem cells to restrain both their proliferation and secretory lineage differentiation. Disruption of this pathway leads to an expansion of tuft cells, enhanced interleukin (IL)-25 production, activation of group 2 innate lymphoid cells (ILC2s) and induction of a type 2 immune response resembling worm expulsion. This phenotype occurs independently of the microbiota but is modulated by the IL-25R–ILC2–IL-13 axis and dietary solid food intake. Our findings expose the enteric nervous system as a critical regulator of epithelial fate decisions and immune balance, complementing established mechanisms that safeguard barrier integrity and mucosal homeostasis.

The peripheral nervous system (PNS) is involved in nociception and gait. The contribution of PNS-resident immune cells to these functions is not fully understood. We identified group 2 innate lymphoid cells (ILC2s) as a distinct immune cell population resident in the PNS, with a unique gene profile facilitating neuron-ILC2 cross-talk. ILC2-deficient mice display PNS dysfunction (hypersensitivity and gait anomalies). These functional deficits are attributed to structural abnormalities in the sciatic nerves of ILC2-deficient mice. ILC2s communicate with dorsal root ganglion neurons via the interleukin-13 (IL-13) signaling pathway to maintain nerve structure and pain thresholds. Loss of the shared IL-4/IL-13 receptor (IL-4R/IL-13R) in neurons results in a phenotype similar to ILC2-deficient mice. Intrathecally administered IL-13 rescues hypersensitivity and gait defects in ILC2-deficient mice, which suggests that this signaling pathway may be therapeutically important. This work therefore identifies a function for ILC2s in regulating the nerve structural integrity and nociceptive functions of the PNS.

The immune system provides multiple layers of protection that extend beyond conventional pathogen defense, including context-dependent modulation of behavior. However, the mechanisms driving these immune-mediated behavioral modifications remain incompletely understood. Here, we demonstrate that group 2 innate lymphoid cells (ILC2s) shape hippocampal synaptic development during early postnatal stages, with lasting effects on adult behavior, learning, and memory. Using flow synaptometry, we identified a selective reduction in hippocampal VGAT⁺ GABAergic/glycinergic inhibitory synapse frequency at postnatal day 15 in ILC2-deficient mice, while the proportions of inhibitory GABAergic (NL2⁺) or excitatory glutamatergic (GluR1⁺) synapses remained unaltered. These synaptic changes occurred without detectable phenotypical changes in cortical and hippocampal microglia. In adulthood, ILC2-deficient mice displayed significant impairments in hippocampus-dependent tasks, such as active place avoidance and operant conditioning, reflecting deficits in learning and memory. Our findings reveal a critical role for ILC2s in the formation of inhibitory synapses in the hippocampus, highlighting the impact of immune signaling on neuronal network maturation during a crucial period of brain development. This early immune-mediated modulation may have lasting effects on neuronal circuitry and cognitive functions that persist into adulthood, emphasizing the long-term implications of neuro-immune interactions for normal cognitive development and function.