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J Exp Med. 2017 Jan;214(1):27-37. doi: 10.1084/jem.20161274. Epub 2016 Dec 23.

Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s.

Author information

1
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 jmoltke@uw.edu richard.locksley@ucsf.edu.
2
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.
3
Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143.
4
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143.
5
Department of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115.

Abstract

Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2 cells) are the primary source of interleukin 5 (IL-5) and IL-13 during type 2 (allergic) inflammation in the lung. In Th2 cells, T cell receptor (TCR) signaling activates the transcription factors nuclear factor of activated T cells (NFAT), nuclear factor κB (NF-κB), and activator protein 1 (AP-1) to induce type 2 cytokines. ILC2s lack a TCR and respond instead to locally produced cytokines such as IL-33. Although IL-33 induces AP-1 and NF-κB, NFAT signaling has not been described in ILC2s. In this study, we report a nonredundant NFAT-dependent role for lipid-derived leukotrienes (LTs) in the activation of lung ILC2s. Using cytokine reporter and LT-deficient mice, we find that complete disruption of LT signaling markedly diminishes ILC2 activation and downstream responses during type 2 inflammation. Type 2 responses are equivalently attenuated in IL-33- and LT-deficient mice, and optimal ILC2 activation reflects potent synergy between these pathways. These findings expand our understanding of ILC2 regulation and may have important implications for the treatment of airways disease.

PMID:
28011865
PMCID:
PMC5206504
DOI:
10.1084/jem.20161274
[Indexed for MEDLINE]
Free PMC Article

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