Division of Allergy & Immunology, Department of Medicine, National Jewish Health, Denver, CO.
Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO.
J Exp Med. 2021 Jul 5;218(7). 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.
反复暴露于 Rag1-/- 小鼠中的 Alternaria 过敏原提取物会产生一种记忆形式，在 3-15 周后的亚阈值回忆挑战时会引发类似哮喘的反应。这种记忆与肺 ICOS+ST2+ILC2s 有关。遗传、药理学、抗体介导的抑制和过继转移确立了 ILC2s 在记忆驱动的哮喘中的重要作用。ATAC-seq 显示了记忆 ILC2s 的独特表观遗传景观，并确定了 Bach2 和 AP1（JunD 和 Fosl2）基序是改变基因可及性的主要驱动因素。scRNA-seq、基因敲除和信号研究表明，反复的变应原应激诱导涉及 Nr4a2、Zeb1、Bach2 和 JunD 的基因抑制程序，以及涉及 Fhl2、FosB、Stat6、Srebf2 和 MPP7 的准备程序在记忆 ILC2s 中。这两个程序之间的相互调节平衡建立并维持记忆。准备程序（例如 Fhl2）可以通过亚阈值同源刺激激活，从而下调抑制剂并激活效应途径以引发记忆驱动的表型。
