Innate lymphoid type 2 cells maintain eosinophils and alternatively activated macrophages in visceral fat via the production of IL-5 and IL-13.

Eosinophils are specialized myeloid cells associated with allergy and helminth infections. Blood eosinophils demonstrate circadian cycling, as described over 80 years ago,1 and are abundant in the healthy gastrointestinal tract. Although a cytokine, interleukin (IL)-5, and chemokines such as eotaxins, mediate eosinophil development and survival,2 and tissue recruitment,3 respectively, the processes underlying the basal regulation of these signals remain unknown. Here, we show that serum IL-5 is maintained by long-lived type 2 innate lymphoid cells (ILC2) resident in peripheral tissues. ILC2 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 constitutive,4 ILC2 co-express IL-5 and IL-13, which is enhanced after caloric intake. The circadian synchronizer vasoactive intestinal peptide (VIP) also stimulates ILC2 through the VPAC2 receptor to release IL-5, linking eosinophil levels with metabolic cycling. Tissue ILC2 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.

The macrophage, a versatile cell type prominently involved in host defense and immunity, assumes a distinct state of alternative activation in the context of polarized type 2 immune responses such as allergic inflammation and helminth infection. This alternatively activated phenotype is induced by the canonical type 2 cytokines interleukin (IL)-4 and IL-13, which mediate expression of several characteristic markers along with a dramatic shift in macrophage metabolic pathways that influence surrounding cells and tissues. We discuss recent advances in the understanding of IL-4- and IL-13-mediated alternatively activated macrophages and type 2 immune responses; such advances have led to an expanded appreciation for functions of these cells beyond immunity, including maintenance of physiologic homeostasis and tissue repair.