ILC2: There’s a New Cell in Town
Authors: Yuan Min Wang, Mahnoor Bakhtiar, Stephen I. Alexander
Journal: Journal of the American Society of Nephrology (2017)

A new type of innate cell that resembles a lymphocyte but lacks a T cell receptor has been identified and is called an innate lymphoid cell (ILC). These cells are found predominantly in epithelial tissues, such as the gut, the lung, and the skin, and have important roles in immunity, infection, and homeostasis.1 ILCs are divided into functional groups ILC1, ILC2, and ILC3 that match cytokines, transcription factors, and surface receptors in classes that have parallels with T helper (Th) subsets Th1, Th2, and Th17.2 ILC2s have much in common with Th2 cells and a major role in protection from disease and possibly, driving autoimmune disease. Given the role of ILC2s in other organs, they are highly likely to have an important role in kidney disease. In this issue of the Journal of the American Society of Nephrology, Riedel et al.3 explore the role of ILC2s in human and mouse kidney as well as disease models. ILCs have recently been recognized as one of the key immune defenses against infection.4,5 The ILC2 subset is thought to play an important role in the pathogenesis of asthma,6 hyper-reactive lung7, and intestinal8 and skin9 diseases through the production of IL-5 and IL-13. IL-33, one of the IL-1 family of cytokines, induces rapid expansion of ILC2 cells. A key feature of mouse and human ILC2s is the expression of the IL-33 receptor ST2. In addition to its various cytokines, ILC2s, like regulatory T cells (Tregs), secrete amphiregulin, which acts to protect tissues.8 However, the action of ILCs in nonbarrier organs, such as kidney, is still largely unknown. Riedel et al.3 show that IL-33 receptor-positive ILC2s form a major subtype of ILCs in both human and murine kidneys. They show that ILCs constitute 0.5%–3% of leukocytes of both human and murine kidney, with IL-33 receptor-positive ILC2s constituting the major subtype. Short-term IL-33 treatment led to sustained expansion of the kidney-residing ILC2s. The expansion seems to be occurring within tissue-resident ILCs rather than in peripheral lymphoid organs. IL-33–induced expansion of renal ILC2 numbers was shown to ameliorate glomerulosclerosis in an adriamycin mouse model of CKD.10 This finding is consistent with other reports suggesting that ILC2s have a major role in maintaining tissue integrity and promoting tissue repair. Immunologic analysis of the kidney in adriamycin nephropathic (AN) mice treated with IL-33 showed a shift in the kidney cytokines from proinflammatory to anti-inflammatory, with an increase in type 2 cytokines IL-5 and IL-13 and a decrease in IFN-γ, TNF-α, and GM-CSF expression. These results suggest a potential therapeutic target in human CKD (Figure 1).Figure 1.: IL-33 treatment induced the expansion of the IL-33 receptor (IL-33R)-positive ILC2s and ameliorated CKD in the AN model. Human ILC2s express the surface markers T1/ST2 (IL-33R), CD80/86, MHCII, CD25, CD127, and CRTH2 and have the transcription factors GATA3 and RORα. IL-33–mediated expansion of ILC2s leads to secretion of IL-5 and IL-13, downregulation of IFN-γ, TNF-α, and GM-CSF, and protection from injury in AN.In this paper, Riedel et al.3 suggested that IL-33–mediated tissue protection requires eosinophils. They further showed the role of eosinophils using adriamycin-treated eosinophil-deficient mice and a lack of protection using IL-33 in these mice. This result suggested that the accumulation of eosinophils in the kidneys is instrumental in the potential therapeutic effect of IL-33. Given that ILC2s produce IL-5, a cytokine that expands eosinophils, it is not unexpected that IL-33 treatment, which expands ILC2s, leads to increased numbers of eosinophils in the kidney. However, the protective effect of the eosinophils is surprising. In general, eosinophils are regarded as proinflammatory and found in both interstitial nephritis and more severe transplant rejection. The mechanisms of this protection are, therefore, clearly of interest. AN is an experimental rodent model of kidney disease that has been studied extensively, and it is an established model in both mice and rats.10 AN is a toxin-induced model of immune-mediated chronic proteinuric kidney disease. It develops after the initial toxic insult of adriamycin and is not a classic antigen-driven, immune-mediated nephritis, such as Heymann nephritis, which is induced by an antigen and an adjuvant. However, the secondary immune response to injury and proteinuria mimics many of the features of human chronic proteinuric renal disease. It will, therefore, be interesting to see whether the protection with IL-33 found in AN extends to other renal models of disease. The release of IL-33 from epithelial cells follows a variety of insults and drives an ILC2 response. Increased IL-33 in the liver has been shown to cause an expansion in liver ILC2s. In this situation, hepatic fibrosis occurs as a result of IL-13 secretion by ILC2s. In atopic dermatitis, ILC2s are also thought to have a pathogenic role.11 It is possible that the interaction of ILC2s with other Th subsets may be crucial to the balance between pathogenic and protective responses. A protective role of Tregs has been recognized in CKD. Also, there seems to be local crosstalk between ILC2s and Tregs as well as Th2 cells.12–14 This duality of IL-33, where it may encourage a protective role via the ILC2/Treg interaction or a damaging role via the ILC2/Th2 interaction, may make its therapeutic use more limited. IL-33 as a therapeutic is still far from proven. There are ongoing reservations about the use of agonist antibodies and cytokines in clinical treatment, in particular because the poor outcomes using anti-CD28 agonist antibodies in human trials have been shown. In this case, although an anti-CD28 antibody was therapeutic in mouse models, it was highly dangerous in humans.15 Although some cytokines, such as low-dose IL-2, have been shown to be clinically effective, this is after much work on dosing and administration issues. This would suggest the need for further animal studies of IL-33 before testing in humans. ILCs occupy an interesting area immunologically between the adaptive immune system of T and B cells and the innate immune system. The ability of ILCs to present antigen to T cells through MHC class-II) allows engagement with both Th2 and Tregs.16 The expression of CD80 and CD86 costimulatory molecules also acts to activate CD4 T cell subsets. Recent work has identified human ILC precursors that are epigenetically set to become ILCs. These migrate to tissues, where they then develop into ILCs and proliferate locally.17 This paper adds a new regulatory or protective immune cell in kidney disease after previous studies have shown protection by adaptive immune cells, CD4 and CD8 Tregs, and γδT cells in kidney disease as well as certain innate cells, including macrophage subsets.12,13 These studies show the potential contribution of renal ILCs in human kidney disease, and a mouse model shows that expansion of ILC2 cells using IL-33 ameliorates AN. This report suggests several new therapeutic avenues for kidney disease on the basis of ILC2s. However, the potential for alternate immune activation by IL-33 or the activation of Th2 effectors by ILC2s may be limiting. It also raises the possibility of a role for ILC2s in other renal conditions. Disclosures None.