Mef2d potentiates type-2 immune responses and allergic lung inflammation

• 成果类型: Article
• 署名作者: Szeto, Aydan C. H.; Clark, Paula A.; Ferreira, Ana C. F.; Heycock, Morgan; Griffiths, Emma L.; Jou, Eric; Mannion, Jonathan; Luan, Shi-Lu; Storrar, Sophie; Knolle, Martin D.; Kozik, Patrycja; Jolin, Helen E.; Fallon, Padraic G.; Mckenzie, Andrew N. J.
• 署名单位: MRC Laboratory Molecular Biology; University of Cambridge; Trinity College Dublin; University of London; Institute of Cancer Research - UK; Royal Marsden NHS Foundation Trust; University of Cambridge
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-14025
• DOI: 10.1126/science.adl0370
• 发表日期: 2024-06-28
• 关键词: innate lymphoid-cells; transcription factor gata3; t-cells; specifies lineage; gene-expression; helper-cells; protein; differentiation; promotes; cloning

摘要

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.