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The Molecular and Epigenetic Mechanisms of Innate Lymphoid Cell (ILC) Memory and its Relevance for Asthma

ABSTRACT: 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 weeks 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 downregulates repressors and activates effector pathways to elicit the memory-driven phenotype.

ORGANISM(S): Mus musculus

PROVIDER: GSE172258 | GEO | 2021/05/31

REPOSITORIES: GEO

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