Mef2d potentiates type-2 immune responses and allergic lung inflammation
Aydan C. H. Szeto, Paula A. Clark, Ana C. F. Ferreira, Morgan W. D. Heycock, Emma L. Griffiths, Eric Jou, Jonathan Mannion, Shi‐Lu Luan, Sophie Storrar, Martin Knolle, Patrycja Kozik, Helen E. Jolin, Padraic G. Fallon, Andrew N. J. McKenzie
Abstract
Innate lymphoid cells (ILCs) and adaptive T lymphocytes promote tissue homeostasis and protective immune responses. Their production depends on the transcription factor GATA3, which is further elevated specifically in ILC2s and T helper 2 cells to drive type-2 immunity during tissue repair, allergic disorders, and anti-helminth immunity. The control of this crucial up-regulation is poorly understood. Using CRISPR screens in ILCs we identified previously unappreciated myocyte-specific enhancer factor 2d (Mef2d)-mediated regulation of GATA3-dependent type-2 lymphocyte differentiation. Mef2d-deletion from ILC2s and/or T cells specifically protected against an allergen lung challenge. Mef2d repressed Regnase-1 endonuclease expression to enhance IL-33 receptor production and IL-33 signaling and acted downstream of calcium-mediated signaling to translocate NFAT1 to the nucleus to promote type-2 cytokine-mediated immunity.