Type 2 innate lymphoid cells control eosinophil homeostasis

Abstract

Eosinophil recruitment to the lung and intestine is regulated by type-2-innate-lymphoid-cell-derived IL-5 and IL-13; IL-5 is shown to be induced by the neuropeptide vasoactive intestinal peptide, which is known to coordinate pancreatic secretion with smooth muscle relaxation in response to feeding. Interleukin-5 (IL-5) is required for bone marrow eosinophil production, whereas IL-13 induces chemoattractant proteins known as eotaxins that recruit eosinophils into inflamed tissue. Richard Locksley and colleagues use a mouse strain that permits fate mapping and deletion of IL-5-producing cells to demonstrate that eosinophil recruitment to the lung and intestine is regulated by type 2 innate lymphoid cell-derived IL-5 and IL-13. IL-5 is induced by vasoactive intestinal peptide, which is known to coordinate pancreatic secretion with smooth muscle relaxation in response to feeding. These findings link eosinophils to basal circadian oscillations through long-lived type 2 innate lymphoid cell activation. Eosinophils are specialized myeloid cells associated with allergy and helminth infections. Blood eosinophils demonstrate circadian cycling, as described over 80 years ago1, and are abundant in the healthy gastrointestinal tract. Although a cytokine, interleukin (IL)-5, and chemokines such as eotaxins mediate eosinophil development and survival2, and tissue recruitment3, respectively, the processes underlying the basal regulation of these signals remain unknown. Here we show that serum IL-5 levels are maintained by long-lived type 2 innate lymphoid cells (ILC2) resident in peripheral tissues. ILC2 cells secrete IL-5 constitutively and are induced to co-express IL-13 during type 2 inflammation, resulting in localized eotaxin production and eosinophil accumulation. In the small intestine where eosinophils and eotaxin are constitutive4, ILC2 cells co-express IL-5 and IL-13; this co-expression is enhanced after caloric intake. The circadian synchronizer vasoactive intestinal peptide also stimulates ILC2 cells through the VPAC2 receptor to release IL-5, linking eosinophil levels with metabolic cycling. Tissue ILC2 cells regulate basal eosinophilopoiesis and tissue eosinophil accumulation through constitutive and stimulated cytokine expression, and this dissociated regulation can be tuned by nutrient intake and central circadian rhythms.