Innate lymphoid cells support regulatory T cells in the intestine through interleukin-2

Lei Zhou, Coco Chu, Fei Teng, Nicholas J. Bessman, Jeremy Goc, Endi K. Santosa, Gregory G. Putzel, Hiroki Kabata, Judith R. Kelsen, Robert N. Baldassano, Manish A. Shah, Robbyn E. Sockolow, Eric Vivier, Gérard Eberl, Kendall A. Smith, Gregory F. Sonnenberg

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21 Citations (Scopus)

Abstract

Interleukin (IL)-2 is a pleiotropic cytokine that is necessary to prevent chronic inflammation in the gastrointestinal tract 1–4 . The protective effects of IL-2 involve the generation, maintenance and function of regulatory T (T reg ) cells 4–8 , and the use of low doses of IL-2 has emerged as a potential therapeutic strategy for patients with inflammatory bowel disease 9 . However, the cellular and molecular pathways that control the production of IL-2 in the context of intestinal health are undefined. Here we show, in a mouse model, that IL-2 is acutely required to maintain T reg cells and immunological homeostasis throughout the gastrointestinal tract. Notably, lineage-specific deletion of IL-2 in T cells did not reduce T reg cells in the small intestine. Unbiased analyses revealed that, in the small intestine, group-3 innate lymphoid cells (ILC3s) are the dominant cellular source of IL-2, which is induced selectively by IL-1β. Macrophages in the small intestine produce IL-1β, and activation of this pathway involves MYD88- and NOD2-dependent sensing of the microbiota. Our loss-of-function studies show that ILC3-derived IL-2 is essential for maintaining T reg cells, immunological homeostasis and oral tolerance to dietary antigens in the small intestine. Furthermore, production of IL-2 by ILC3s was significantly reduced in the small intestine of patients with Crohn’s disease, and this correlated with lower frequencies of T reg cells. Our results reveal a previously unappreciated pathway in which a microbiota- and IL-1β-dependent axis promotes the production of IL-2 by ILC3s to orchestrate immune regulation in the intestine.

Original languageEnglish
Pages (from-to)405-409
Number of pages5
JournalNature
Volume568
Issue number7752
DOIs
Publication statusPublished - 2019 Apr 18
Externally publishedYes

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ASJC Scopus subject areas

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Cite this

Zhou, L., Chu, C., Teng, F., Bessman, N. J., Goc, J., Santosa, E. K., Putzel, G. G., Kabata, H., Kelsen, J. R., Baldassano, R. N., Shah, M. A., Sockolow, R. E., Vivier, E., Eberl, G., Smith, K. A., & Sonnenberg, G. F. (2019). Innate lymphoid cells support regulatory T cells in the intestine through interleukin-2. Nature, 568(7752), 405-409. https://doi.org/10.1038/s41586-019-1082-x