A mechanism to initiate emergency type 2 myelopoiesis

  • Nature. 2026 May;653(8113):212-220. doi: 10.1038/s41586-026-10256-6.
Alexandre Fagnan  1 ,  Cristina Di Genua  1 ,  Yiran Meng  1 ,  Roy Drissen  1 ,  Zishan Zhang  1 ,  Bowen Zhang  1 ,  Padraic G Fallon  2 ,  Vassilis Pachnis  3 ,  Erika J Mancini  4 ,  Fränze Progatzky  3  5 ,  Claus Nerlov  6
Affiliations
  • 1. MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
  • 2. School of Medicine, Trinity College Dublin, Dublin, Ireland.
  • 3. Nervous System Development and Homeostasis Laboratory, Francis Crick Institute, London, UK.
  • 4. School of Life Sciences and Sussex Drug Discovery Centre, University of Sussex, Brighton, UK.
  • 5. Kennedy Institute of Rheumatology, Oxford, UK.
  • 6. MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. [email protected].
PMID: 41813898 DOI: 10.1038/s41586-026-10256-6
Abstract

Immune responses to parasite Infection involve the increased production of basophils and eosinophils. These two myeloid cell types have key roles in type 2 anti-parasite immunity1 and rely on GATA family transcription factors for their specification2,3. The first committed step in basophil and eosinophil production is generation of basophil-eosinophil-mast cell progenitors (BEMPs) from oligopotent erythroid-primed multipotent progenitors (EMPPs). However, it is not well established how immune responses act on progenitors to initiate type 2 myelopoiesis. Here we show that Infection with the helminth Heligmosomoides polygyrus increases EMPP commitment to myeloid fate at the expense of erythropoiesis. Upon Infection with H. polygyrus, the IL-33 alarmin accumulated in the bone marrow, causing EMPPs to upregulate the GATA co-factor LMO4 and preferentially differentiate into myeloid cells. LMO4 was sufficient to instruct myeloid fate in EMPPs by interacting with GATA2, displacing the FOG1 co-factor and redistributing GATA binding from megakaryocyte-erythroid-specific to basophil, eosinophil and mast cell (BEM)-specific chromatin. Accordingly, mice carrying a GATA2 mutation that selectively impairs the LMO4-GATA2 interaction were deficient in GATA factor allocation to BEM chromatin, myeloid lineage commitment, basophil and eosinophil production, and Parasite control. This identifies LMO4 as an IL-33-regulated master regulator of type 2 myelopoiesis, and transcription factor reallocation as a mechanism of lineage commitment.

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