Open AccessThe molecular and epigenetic mechanisms of innate lymphoid cell (ILC) memory and its relevance for asthma
Author(s) -
Mukesh Verma,
Lidia Michalec,
Anand Sripada,
Jerome T McKay,
Kapil Sirohi,
Divya Verma,
Dipa Sheth,
Richard J. Martin,
Nathan Dyjack,
Max A. Seibold,
Jennifer R. Knapp,
Ting-Hui Tu,
Brian P. O’Connor,
M. Górska,
Rafeul Alam
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20201354
Subject(s) - epigenetics , biology , immunology , fosb , microbiology and biotechnology , cancer research , genetics , gene , gene expression
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.