Thomas Plum

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 physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance^1–3. Here, we show that antigen-specific avoidance behaviour in inbred mice^4,5 is critically dependent on mast cells; hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity.

B cell antigen receptor (BCR) signaling is critical for B cell development and activation. Using mass spectrometry, we identified a protein kinase D–interacting substrate of 220 kD (Kidins220)/ankyrin repeat–rich membrane-spanning protein (ARMS) as a novel interaction partner of resting and stimulated BCR. Upon BCR stimulation, the interaction increases in a Src kinase–independent manner. By knocking down Kidins220 in a B cell line and generating a conditional B cell–specific Kidins220 knockout (B-KO) mouse strain, we show that Kidins220 couples the BCR to PLCγ2, Ca²⁺, and extracellular signal-regulated kinase (Erk) signaling. Consequently, BCR-mediated B cell activation was reduced in vitro and in vivo upon Kidins220 deletion. Furthermore, B cell development was impaired at stages where pre-BCR or BCR signaling is required. Most strikingly, λ light chain–positive B cells were reduced sixfold in the B-KO mice, genetically placing Kidins220 in the PLCγ2 pathway. Thus, our data indicate that Kidins220 positively regulates pre-BCR and BCR functioning.