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Regulation of type 2 innate lymphoid cells at barrier sites
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Type 2 innate lymphoid cells (ILC2s) are essential for the immune response to helminthic parasites, in allergy settings and for the control of adipose tissue homeostasis. However, how ILC2s perceive environmental cues and integrate signals to maintain tissue homeostasis remains poorly understood. Here we show that adipose tissue ILC2s are controlled by the sympathetic tone through the production of neurotrophic factors by mesenchymal stromal cells (MSCs). The gonadal adipose tissue is densely innervated by sympathetic neurons that have discrete central nervous system origins. Ablation of one of such brain centers coordinating the sympathetic output to the adipose tissue, the paraventricular nucleus of the hypothalamus, results in decreased ILC2 function. Thus, ILC2 function in the gonadal adipose tissue is controlled by brain-derived nervous system signals. We dissected the mechanisms behind this regulation, finding that activation of sympathetic neurons leads to an increase in cytokine-producing ILC2s independently of direct β2 adrenergic receptor signaling. Instead, β2 adrenergic receptor activation in a population of MSCs leads to the production of neurotrophic factors by these cells. Conversely, sympathetic ablation or inactivation reduces cytokine-producing ILC2s and production of neurotrophic factors by MSCs. These neurotrophic factors, namely glial derived neurotrophic factor (GDNF), has been described as limiting obesity in previous research. GDNF and the glial family ligands produced by MSCs signal through the tyrosine kinase receptor RET. GDNF activates RET on ILC2s, stimulating cytokine production. Deleting RET signaling on these cells results in reduced frequencies of cytokine-producing ILC2s and RET activation as the opposite effect. Ultimately, RET-dependent cell-autonomous signals on ILC2s control adipose tissue physiology. This is demonstrated by the absence of RET in ILC2s which leads to increased susceptibility to high fat diet-induced obesity with systemic consequences. This work sheds light into a novel neuro-mesenchymal-immune regulatory axis that integrates environmental sensing by the nervous system impacting on adipose tissue homeostasis through the control of ILC2 function by MSCs.