Highlights d 3D imaging defines ILC2 niches in perivascular regions of multiple tissues d ILC2s localize with fibroblast-like adventitial stromal cells (ASCs) d Lung ASCs produce IL-33 and TSLP to support ILC2 and Th2s d ILC2s promote ASC expansion and IL-33 production after helminth infection

SUMMARY MicroRNAs (miRNAs) are important regulators of cell fate decisions in immune responses. They act by coordinate repression of multiple target genes, a property that we exploited to uncover regulatory networks that govern T helper-2 (Th2) cells. A functional screen of individual miRNAs in primary T cells uncovered multiple miRNAs that inhibited Th2 cell differentiation. Among these were miR-24 and miR-27, miRNAs coexpressed from two genomic clusters, which each functioned independently to limit interleukin-4 (IL-4) production. Mice lacking both clusters in T cells displayed increased Th2 cell responses and tissue pathology in a mouse model of asthma. Gene expression and pathway analyses placed miR-27 upstream of genes known to regulate Th2 cells. They also identified targets not previously associated with Th2 cell biology which regulated IL-4 production in unbiased functional testing. Thus, elucidating the biological function and target repertoire of miR-24 and miR-27 reveals regulators of Th2 cell biology.

Peripheral nerve injury-induced neuropathic pain is a chronic and debilitating condition characterized by mechanical hypersensitivity. We previously identified microglial activation via release of colony stimulating factor 1 (CSF1) from injured sensory neurons as a mechanism contributing to nerve injury-induced pain. Here we show that intrathecal administration of CSF1, even in the absence of injury, is sufficient to induce pain behavior, but only in male mice. Transcriptional profiling and morphologic analyses after intrathecal CSF1 showed robust immune activation in male but not female microglia. CSF1 also induced marked expansion of lymphocytes within the spinal cord meninges, with preferential expansion of regulatory T-cells (Tregs) in female mice. Consistent with the hypothesis that Tregs actively suppress microglial activation in females, Treg deficient (Foxp3DTR) female mice showed increased CSF1-induced microglial activation and pain hypersensitivity equivalent to males. We conclude that sexual dimorphism in the contribution of microglia to pain results from Treg-mediated suppression of microglial activation and pain hypersensitivity in female mice.

Tuft cells are a type of rare epithelial cell present in the respiratory and intestinal tracts, among other locations in humans, rodents, and reptiles.In addition to other functions, tuft cells use components of the taste transduction system to survey the extracellular environment and play a role in pathogen defense by stimulating neighboring ciliated epithelial cells to secrete antimicrobial products.The dominant epithelial source of interleukin-25 and an important source of cysteinyl leukotrienes in the airway, tuft cells have been implicated as upstream agents in type 2 inflammation in chronic rhinosinusitis with nasal polyps and asthma.An important role of tuft cells is to act as a bridge between innate and adaptive immune responses in driving type 2 inflammation in the airway.Tuft cells cluster into subpopulations, which could play diverse roles in the pathophysiology of different diseases and possibly utilize immunomodulatory effector molecules outside of type 2 inflammatory cytokines.Further studies are needed, particularly on the use of better genetic tools for tracking tuft cell subpopulations to investigate the extent to which different subpopulations of tuft cells contribute to chronic inflammatory diseases.

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