Abstract
Innate lymphoid cells are central to the regulation of immunity at mucosal barrier sites, with group 2 innate lymphoid cells (ILC2s) being particularly important in type 2 immunity. In this study, we demonstrate that microRNA(miR)-142 plays a critical, cell-intrinsic role in the homeostasis and function of ILC2s. Mice deficient for miR-142 expression demonstrate an ILC2 progenitor-biased development in the bone marrow, and along with peripheral ILC2s at mucosal sites, these cells display a greatly altered phenotype based on surface marker expression. ILC2 proliferative and effector functions are severely dysfunctional following Nippostrongylus brasiliensis infection, revealing a critical role for miR-142 isoforms in ILC2-mediated immune responses. Mechanistically, Socs1 and Gfi1 expression are regulated by miR-142 isoforms in ILC2s, impacting ILC2 phenotypes as well as the proliferative and effector capacity of these cells. The identification of these novel pathways opens potential new avenues to modulate ILC2-dependent immune functions.
Highlights
Araki, Jagath Kasturiarachchi, Chela James, Tariq Enver, Rachael Nimmo, Rita Reis, Jane K
MiR-142 is highly expressed by cells of the hematopoietic lineage, including hematopoietic stem cells which are often studied by isolating the c-Kit1 (Kit1) lineage Sca-11 population (KLS) found in the bone marrow (BM)
Markers of the group 2 ILC (ILC2) lineage were among the predicted overexpressed transcripts (Supplemental Fig. 1D) among other genes reported to contribute to an ILC2-like transcriptional signature (Supplemental Fig. 1E) (14, 3439)
Summary
Following analysis of RNA-sequencing data generated from the KLS population of mice with a genomic CRISPR-mediated deletion of miR-142 (B6-Mir142em2Card), our model predicted 118 genes to be differentially overexpressed and 101 genes to be underexpressed in miR142deficient samples compared with controls; these gene sets were enriched for gene ontology terms related to numerous aspects of immune system regulation and function (Supplemental Fig. 1AC). A striking observation was that Mir142/ ILC2s in these peripheral sites displayed a vastly altered cell surface phenotype compared with WT controls, matching observations in BM Mir142/ ILC2p
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