Editorial: New tricks for innate lymphoid cells

ILCs are an emerging family of innate immune cells that exhibit phenotypic and functional heterogeneity that is remarkably similar to effector subsets of CD4 Th cells [1, 2]. As such, ILCs can be placed into three groups based on expression of cytokines, cytokine receptors, and transcription factors, including T-bet Group 1 ILCs that are comparable with Th1 cells, GATA3 Group 2 ILCs that are comparable with Th2 cells, and retinoic acid receptor-related orphan receptor t Group 3 ILCs that are comparable with Th17 cells and Th22 cells [1, 2]. Early studies investigating the functional potential of ILCs have identified that similar to CD4 T cell effector subsets, ILCs can orchestrate context-dependent immunity or tissue inflammation via production of canonical effector cytokines. For example, Group 3 ILCs can promote IL-17or IL-22-dependent antibacterial immunity and intestinal inflammation, whereas Group 2 ILCs can promote IL-5or IL-13-dependent antiparasite immunity and allergic inflammation [3–7]. However, whether ILC subsets also have novel functions that extend beyond rapid expression of classical CD4 T cell-associated effector cytokines remains poorly understood. In this issue of the Journal of Leukocyte Biology, Locksley and colleagues [8] identify that in addition to Th2 cell-associated cytokines IL-5 and IL-13, Group 2 ILCs express the enzyme arginase-1 in the lungs of mice. Arginase-1 is a manganese metalloenzyme that catalyzes the conversion of the amino acid L-arginine into L-ornithine and urea [9, 10]. This enzymatic reaction is the final step of the urea cycle that is essential for hepatocyte conversion of harmful ammonia into urea prior to excretion from the host. Expression of arginase-1 in the liver is essential to maintain mammalian homeostasis, and mice genetically lacking Arg1 develop symptoms of hyperammonemia and die soon after birth [9, 10]. In addition to hepatocytes, arginase-1 is expressed within the mammalian immune system in response to parasites or allergens. Whereas not expressed in T cell populations, arginase-1 is expressed in myeloid cells during type 2 immunity or inflammation and is a hallmark of AAMacs along with other classical AAMac-associated genes, Ym-1 and RELM [10, 11]. Intriguingly, Locksley and colleagues [8] identify that unlike AAMac expression of arginase-1, which is induced by IL-4or IL-13-mediated activation of STAT6 [9, 10], ILC-intrinsic expression of arginase-1 occurs independently of STAT6, suggesting a novel pathway for induction. Consistent with this, Group 2 ILCs were found to constitutively express arginase-1 in multiple tissues derived from naive mice, including the lung, spleen, mesenteric LN, and small intestine. The cellular and molecular signals regulating constitutive ILC-intrinsic arginase-1 expression remain elusive; however, it was identified that IL-33–IL33R interactions in vivo could expand STAT6-independent arginase-1 ILCs and STAT6-dependent arginase-1 AAMacs. These data suggest that IL-33 can orchestrate arginase-1 responses indirectly by promoting expansion of arginase-1 Group 2 ILCs and mediating AAMac differentiation via STAT6 signaling from ILC-derived IL-13or IL-5-mediated recruitment of IL-4 eosinophils (Fig. 1). Further studies will be necessary to define the STAT6-independent pathways responsible for ILC-intrinsic expression of arginase-1 in the steady state and following infection or inflammation. Some potential insight may be drawn from studies identifying a novel pathway of arginase-1 expression in macrophages following Mycobacterium tuberculosis infection, which involves TLR/MyD88 stimulation and STAT3dependent signals [12, 13]. Intriguingly, this STAT3-regulated pathway did not induce coexpression of other classical AAMac-associated genes, which is more similar to the low or absent coexpression of Ym-1 and RELM in arginase-1 Group 2 ILCs described by Locksley and colleagues [8]. AAMac-intrinsic arginase-1 expression has been proposed to be a critical regulator of immunity and tissue fibrosis in response to parasitic infection or allergic inflammation [9, 10]. These properties are a function of L-arginine metabolism by arginase-1 AAMacs. For example, AAMac-derived arginase-1 can counter-regulate other enzymes requiring the L-arginine substrate, including NOS that catalyzes production of ROS and play a critical role in immunity to bacteria and tumors. Furthermore, a byproduct of L-arginine metabolism is L-ornithine, which can be processed further to L-proline, a critical amino acid for collagen synthesis and fibrotic responses. In contrast to these proposed functions for AAMac-intrinsic arginse-1, Locksley and colleagues [8] demonstrate that genetic deletion of arginase-1