title: Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s.
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.
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 jmoltke@uw.edu richard.locksley@ucsf.edu.|Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.|Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Jakob
authors.identifier: 0000-0003-2894-3353
authors.initials: J
authors.lastname: von Moltke
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143.|Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.|Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Claire E
authors.initials: CE
authors.lastname: O'Leary
authors.affiliation: Department of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Nora A
authors.initials: NA
authors.lastname: Barrett
authors.affiliation: Department of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Kanaoka
authors.affiliation: Department of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: K Frank
authors.identifier: 0000-0002-9955-2432
authors.initials: KF
authors.lastname: Austen
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 jmoltke@uw.edu richard.locksley@ucsf.edu.|Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.|Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Locksley
mesh_terms: D000818:Animals; D004357:Drug Synergism; D006706:Homeostasis; D000067596:Interleukin-33 / Q000494:pharmacology*; D015289:Leukotrienes / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000067596:Interleukin-33; D015289:Leukotrienes; D050778:NFATC Transcription Factors