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.

Purpose of reviewThe purpose of this review is to provide a synthesis of recent discoveries about type-2 innate lymphoid cells, especially, as they relate to the pathogenesis of asthma. Recent findingsWe focused on features and characteristics of type-2 innate lymphoid cells (ILC2s) that distinguish them from other type-2 cells, especially Th2 cells. We collected and reviewed data related to human asthma and airway ILC2s. We examined the concept of ILC2 memory and trained immunity. We also analyzed steroid resistance of ILC2s, which is relevant for steroid-resistant asthma.

BackgroundILC2s are capable of generating memory. The mechanism of memory induction and memory-driven effector function (trained immunity) in ILC2s is unknown.ObjectiveNFκB1 is preferentially expressed at a high level in ILC2s. We examined the role of NFkB1 in memory induction and memory-driven effector function in a mouse model of asthma.MethodsIntranasal administration of Alternaria, flexivent, ELISA, histology, real-time PCR, western blot, flow cytometry and immunofluorescence staining.ResultsNFκB1 was essential for the effector phase of memory-driven asthma. NFκB1 was critical for IL33 production, ILC2 generation, and production of type-2 cytokines, which resulted in eosinophilic inflammation and other features of asthma. NFκB1 induction of type-2 cytokines in ILC2s was independent of GATA3. NFκB1 was important for allergen induction of ILC3s and FoxP3+ Tregs. NFκB1 did not affect Th2 cells or their cytokine production. In contrast to its protagonistic role in the effector phase, NFκB1 had an antagonistic role in the memory phase. NFκB1 inhibited allergen-induced upregulation of memory-associated repressor and preparedness genes in ILC2s. NFκB1 upregulated RUNX1. NFκB1 formed a heterodimer with RUNX1 in ILC2s.ConclusionsNFκB1 positively regulated the effector phase but inhibited the induction phase of memory. The foregoing pointed to an interdependent antagonism between the memory induction and the memory effector processes. The NFκB1-RUNX1 heterodimer represented a non-canonical transcriptional activator of type-2 cytokines in ILC2s.

No abstract

Innate lymphoid cells have the capability to communicate with other immune cell types to coordinate the immune system functioning during homeostasis and inflammation. However, these cells behave differently at the functional level, unlike T cells, these cells do not need antigen receptors for activation because they are activated by the interaction of their receptor ligation. In hematopoietic stem cell transplantation (HSCT), T cells and NK cells have been extensively studied but very few studies are available on ILCs. In this review, an attempt has been made to provide current information related to NK and ILCs cell-based stem cell therapies and role of the stem cells in the regulation of ILCs as well. Also, the latest information on the differentiation of NK cells and ILCs from CD34+ hematopoietic stem cells is covered in the article.