The molecular and epigenetic mechanisms of innate lymphoid cell (ILC) memory and its relevance for asthma

J Exp Med. 2021 Jul 5;218(7):e20201354. doi: 10.1084/jem.20201354. Epub 2021 Jun 2.


Repetitive exposure of Rag1-/- mice to the Alternaria allergen extract generated a form of memory that elicited an asthma-like response upon a subthreshold recall challenge 3-15 wk later. This memory was associated with lung ICOS+ST2+ ILC2s. Genetic, pharmacologic, and antibody-mediated inhibition and adoptive transfer established an essential role for ILC2s in memory-driven asthma. ATAC-seq demonstrated a distinct epigenetic landscape of memory ILC2s and identified Bach2 and AP1 (JunD and Fosl2) motifs as major drivers of altered gene accessibility. scRNA-seq, gene knockout, and signaling studies suggest that repetitive allergenic stress induces a gene repression program involving Nr4a2, Zeb1, Bach2, and JunD and a preparedness program involving Fhl2, FosB, Stat6, Srebf2, and MPP7 in memory ILC2s. A mutually regulated balance between these two programs establishes and maintains memory. The preparedness program (e.g., Fhl2) can be activated with a subthreshold cognate stimulation, which down-regulates repressors and activates effector pathways to elicit the memory-driven phenotype.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer / methods
  • Allergens / immunology
  • Alternaria / immunology
  • Animals
  • Asthma / immunology*
  • Down-Regulation / immunology
  • Epigenesis, Genetic / immunology*
  • Female
  • Immunity, Innate / immunology*
  • Immunologic Memory / immunology*
  • Lymphocytes / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout


  • Allergens