Mef2d potentiates type-2 immune responses and allergic lung inflammation
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...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2024-06, Vol.384 (6703), p.eadl0370 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1126/science.adl0370 |
| format | Article |
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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.</description><identifier>ISSN: 0036-8075</identifier><identifier>ISSN: 1095-9203</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.adl0370</identifier><identifier>PMID: 38935708</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Allergens - immunology ; Allergies ; Animal models ; Animals ; Antibodies ; Antiparasitic agents ; Boolean ; Calcium ; Calcium Signaling ; Calcium signalling ; CD4 antigen ; Cell culture ; Cell Differentiation ; CRISPR ; Cytokines ; Deletion ; Dendritic cells ; Epitopes ; GATA3 Transcription Factor - genetics ; GATA3 Transcription Factor - metabolism ; Gene expression ; Gene regulation ; Genes ; Helper cells ; Hypersensitivity - immunology ; Immune response ; Immune system ; Immunity ; Immunity, Innate ; Individualized Instruction ; Inflammation ; Interleukin 13 ; Interleukin 7 receptors ; Interleukin-1 Receptor-Like 1 Protein ; Interleukin-33 - metabolism ; Interleukins ; Intracellular signalling ; Logic circuits ; Logical Thinking ; Lung - immunology ; Lungs ; Lymphocytes ; Lymphocytes - immunology ; Lymphocytes T ; Macrophages ; Measles ; MEF2 Transcription Factors - genetics ; MEF2 Transcription Factors - metabolism ; Mice ; Mice, Inbred C57BL ; NF-AT protein ; NFATC Transcription Factors - metabolism ; Pneumonia - immunology ; Protein folding ; Proteins ; Signal transduction ; Th2 Cells - immunology ; Therapeutic targets ; Transcription factors</subject><ispartof>Science (American Association for the Advancement of Science), 2024-06, Vol.384 (6703), p.eadl0370</ispartof><rights>Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. 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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.</description><subject>Allergens - immunology</subject><subject>Allergies</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antiparasitic agents</subject><subject>Boolean</subject><subject>Calcium</subject><subject>Calcium Signaling</subject><subject>Calcium signalling</subject><subject>CD4 antigen</subject><subject>Cell culture</subject><subject>Cell Differentiation</subject><subject>CRISPR</subject><subject>Cytokines</subject><subject>Deletion</subject><subject>Dendritic cells</subject><subject>Epitopes</subject><subject>GATA3 Transcription Factor - genetics</subject><subject>GATA3 Transcription Factor - metabolism</subject><subject>Gene expression</subject><subject>Gene regulation</subject><subject>Genes</subject><subject>Helper cells</subject><subject>Hypersensitivity - 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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.</abstract><cop>United States</cop><pub>The American Association for the Advancement of Science</pub><pmid>38935708</pmid><doi>10.1126/science.adl0370</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | Science (American Association for the Advancement of Science), 2024-06, Vol.384 (6703), p.eadl0370 |
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| subjects | Allergens - immunology Allergies Animal models Animals Antibodies Antiparasitic agents Boolean Calcium Calcium Signaling Calcium signalling CD4 antigen Cell culture Cell Differentiation CRISPR Cytokines Deletion Dendritic cells Epitopes GATA3 Transcription Factor - genetics GATA3 Transcription Factor - metabolism Gene expression Gene regulation Genes Helper cells Hypersensitivity - immunology Immune response Immune system Immunity Immunity, Innate Individualized Instruction Inflammation Interleukin 13 Interleukin 7 receptors Interleukin-1 Receptor-Like 1 Protein Interleukin-33 - metabolism Interleukins Intracellular signalling Logic circuits Logical Thinking Lung - immunology Lungs Lymphocytes Lymphocytes - immunology Lymphocytes T Macrophages Measles MEF2 Transcription Factors - genetics MEF2 Transcription Factors - metabolism Mice Mice, Inbred C57BL NF-AT protein NFATC Transcription Factors - metabolism Pneumonia - immunology Protein folding Proteins Signal transduction Th2 Cells - immunology Therapeutic targets Transcription factors |
| title | Mef2d potentiates type-2 immune responses and allergic lung inflammation |
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