ILC2 activation by leukotrienes: NFAT joins the team

• Published in: The Journal of immunology (1950) 2018-05, Vol.200 (1_Supplement), p.119-119.6
• Main Authors: von Moltke, Jakob, O’Leary, Claire E., Barrett, Nora, Kanaoka, Yoshihide, Austen, K. Frank, Locksley, Richard M.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.200.Supp.119.6

The initiation and maintenance of type 2 (allergic) immune responses in the lung requires production of the type 2 cytokines interleukin (IL)-4, IL-5, IL-13, and IL-9, which together drive eosinophilia and other hallmarks of type 2 inflammation. Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2) are the primary source of these cytokines. In Th2s, T cell receptor (TCR) signaling activates the transcription factors NFAT, AP-1, and NFκB, which cooperate to induce type 2 cytokines. ILC2s lack a TCR and respond instead to locally produced cytokines such as IL-33. While IL-33 induces AP-1 and NFκB, NFAT signaling has not been described in ILC2s and it remains unclear how maximal cytokine production is achieved in vivo. Here, we report the non-redundant NFAT-dependent role of lipid-derived leukotrienes in the activation of lung ILC2s. Using cytokine reporter and leukotriene-deficient mice in innate and adaptive models of type 2 airway inflammation, we find that while loss of leukotriene B4 or cysteinyl leukotriene signaling alone has modest effects, deletion of both pathways markedly diminishes ILC2 activation and eosinophilia. Type 2 responses are similarly attenuated in IL-33- and leukotriene-deficient mice, and optimal ILC2 activation reflects potent synergy between these pathways. We hypothesize that ILC2s integrate multiple signals as a substitute for TCR signaling. These findings therefore expand our understanding of ILC2 regulation and may have important implications for the treatment of airways disease.