Research Theme

7. Regulatory mechanisms for the activation of group 2 innate lymphoid cells

Kazuyo Moro1, Hiroki Kabata1,2, Satoshi Koga1, and Shigeo Koyasu3
1Laboratory for Innate Immune Systems, RIKEN IMS, 2Department of Medicine, Keio University School of Medicine, 3Laboratory for Immune Cell Systems, RIKEN IMS

Recent studies have identified novel lymphocytes that do not express Rag-dependent antigen specific receptors but are able to produce large amounts of cytokines, collectively called innate lymphoid cells (ILC). ILC are classified into three groups based of their cytokine expression patterns: group 1 ILC (ILC1) producing IFNγ group 2 ILC (ILC2) producing IL-5 and IL-13, and group 3 ILC (ILC3) producing IL-17 and IL-22. Among ILCs, ILC2 were originally identified in adipose tissues by our group and were named as natural helper cells. ILC2 were later found in various tissues in both mouse and human. Since ILC2 were originally identified in adipose tissues [1], it has been of interest to study their role in the regulation of homeostasis in adipose tissues. Adipose tissues contain two types of macrophages: M1 macrophages or inflammatory macrophages producing pro-inflammatory cytokines such as IL-1β and TNFα, and M2 macrophages or anti-inflammatory macrophages expressing a high amounts of arginase. M2 macrophages are induced by type 2 cytokine such as IL-4 and IL-13, it is likely that ILC2 contributes to the generation of M2 or anti-inflammatory macrophages.

Here we examined the regulatory mechanisms of ILC2 functions in vivo and found that both type I and type II IFNs, and interleukin-27 (IL-27) strongly suppressed proliferation and function of ILC2s in a STAT1 transcription factor-dependent manner. ILC2-mediated lung inflammation was enhanced in the absence of IFNγ receptor on ILC2s in vivo, demonstrating the importance of endogenous IFNγ in the termination of ILC2-mediated inflammation. IFNγ effectively suppressed the function of ILC2s but not recently described “inflammatory ILC2” induced by IL-25 [2], and IL-27 suppressed ILC2s but not TH2 cells in Alternaria-induced lung inflammation. Our results demonstrate that IFN- and IL-27-mediated suppression is a negative feedback mechanism for ILC2 function in vivo. This work has been published in 2016 (Moro et al. “Interferon and interleukin-27 antagonize group 2 innate lymphoid cell function and type 2 innate immune responses”, Nat. Immunol. 17, 76-86).

Figure. Schematic summary of the negative feedback mechanisms fort ILC2 functions.
IFNγ from innate natural killer (NK) cells and adaptive T helper type 1 (Th1) cells and IL-27 from antigen presenting dendritic cells (DC) suppress ILC2 functions. This is similar to the previously described negative feedback mechanisms for T helper type 2 (Th2) cells.

[1] Moro, K., Yamada, T., Tanabe, M., Takeuchi, T., Ikawa, T., Kawamoto, H., Furusawa, J.-I., Ohtani, M., Fujii, H. and Koyasu, S. Innate production of Th2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540-544 (2010).
[2] Huang, Y., Guo, L., Qiu, J., Chen, X., Hu-Li, J., Siebenlist, U., Williamson, P.R., Urban, J.F. Jr, Paul, W.E. IL-25-responsive, lineage-negative KLRG1hi cells are multipotential 'inflammatory' type 2 innate lymphoid cells. Nat Immunol. 16, 161-169 (2015).