ON THE COVER
Li et al. apply mass cytometry to delineate the fetal gut innate lymphoid cell (ILC) population and use a t-SNE-based approach to predict potential differentiation trajectories. This image represents the composition of the ILC compartment in the individual fetal intestines. The image was taken from the original manuscript and modified by the JEM editorial office. See page 1287.
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Chiang et al. make a notable contribution in Alzheimer disease (AD) therapeutics in a thorough and rigorous study demonstrating superior efficacy of dual therapy against Aβ in a mouse model of amyloid β deposition.
In this issue of JEM, Zhang et al. show that the suppressive epigenetic enzyme Ezh2 is an important regulator of macrophage activation. The absence of Ezh2 leads to reduced cytokine secretion and suppresses macrophage-dependent disease development. They identify the antiinflammatory factor Socs3 as an important target for Ezh2 and thus show that regulation of suppressive histone modifications controls macrophage activation in disease.
Type I interferons have been implicated in the pathogenesis of tuberculosis. Herein, Moreira-Teixeira et al. discuss mechanistic and contextual factors that determine the role of type I interferons during Mycobacterium tuberculosis infection, from human disease to experimental models of tuberculosis.
The cGAS–cGAMP–STING pathway mediates immune and inflammatory responses to cytosolic DNA. This review summarizes recent findings on how genomic instability leads to cGAS activation and how this pathway critically connects DNA damage to autoinflammatory diseases, cellular senescence, and cancer.
Brief Definitive Report
This study by Stockstill et al. demonstrates that bortezomib-induced neuropathic pain is driven by S1P receptor 1 (S1PR1) activation in spinal cord astrocytes. Disrupting spinal astrocyte S1PR1 signaling attenuates neuropathic pain by reducing neuroinflammation and presynaptic glutamate release.
Selective inhibition of the p38α MAPK–MK2 axis inhibits inflammatory cues including inflammasome priming signals
A unique p38α MAPK–MK2 pathway inhibitor, CDD-450, is used to uncover the function of this protein complex in inflammasome priming signals. Importantly, CDD-450 is as efficacious as global p38α MAPK inhibitors in decreasing inflammation in disease models.
Despite the numerous cellular functions attributed to the scaffolding protein CIN85, Keller et al. show that an inactivating germline deletion within the human CIN85 gene causes a remarkably specific defect in the activation of B lymphocytes, preventing proper immune responses.
Megakaryocytes are known for hematopoietic stem cell (HSC) regulation. Here, Jiang et al. show that megakaryocytes cooperate with Schwann cells in bone marrow niche and that SHP-1 regulates HSC quiescence by coordinating TGF-β signaling in megakaryocyte niche.
Combination anti-Aβ treatment maximizes cognitive recovery and rebalances mTOR signaling in APP mice
Chiang et al. show that combining two complementary approaches for Aβ reduction improved cognitive function in a mouse model of amyloidosis relative to either treatment alone. Efficacy corresponded with restoration of mTOR signaling, TFEB expression, and autophagic flux, suggesting additional targets for future polytherapy in AD.
H3K27me3 is known to silence gene expression. Zhang et al. reveal that, rather than functioning as a repressor, Ezh2 or H3K27me3 specifically mediates toll-like receptor (TLR)-induced proinflammatory responses in macrophages/microglia, in which Ezh2 directly targets Socs3, consequently mediates TLR-induced NF-κB activation, and facilitates autoimmune inflammation.
Li et al. apply mass cytometry to delineate the fetal gut innate lymphoid cell (ILC) population and utilize a t-SNE–based approach to predict potential differentiation trajectories. They identify an int-ILC subset that differentiates into NK cells or ILC3s in vitro.
Symbiotic relationships help shape immune fitness. Chen et al. demonstrate that microbial symbionts influence host immunity by enriching frequencies of antibacterial specificities within the naive B cell receptor repertoire and that this may have consequences for mucosal and systemic immunity.
Durai et al. demonstrate that the less severe DC deficiency in Flt3–/– mice compared to Flt3l–/– mice is due to the enhanced sensitivity of Flt3–/– progenitors to compensatory cytokines that support DC development.
Germinal center (GC) B cell response is critical for pathogen protection. Chen et al. find that Uhrf1 is up-regulated by the c-Myc–AP4 axis and plays an essential role in GC B cell expansion and affinity maturation.
Bcl11b, a novel component of GATA3-containing transcriptional complex, inhibits Th2 cytokine production both in vitro and in vivo. Genome-wide analysis indicates that the Bcl11b/GATA3 complex not only limits the magnitude of Th2 response but also suppresses Th1-specific gene expression.
Thrombopoietin protects hematopoietic stem cells from retrotransposon-mediated damage by promoting an antiviral response
Propagation of retrotransposons induces genomic instability. Their roles in HSCs remain poorly studied. Barbieri et al. show that retrotransposon expression and mobilization are involved in long-lasting HSC impairment upon irradiation. These effects are counteracted by the self-renewal cytokine THPO through induction of interferon-like response.
Termination of T cell priming relies on a phase of unresponsiveness promoting disengagement from APCs and T cell division
Bohineust et al. establish that recently activated T cells exhibit a phase of unresponsiveness associated with a defect in calcium entry. This stage was essential to terminate priming, distracting T cells from APCs, and favoring their clonal expansion.
Technical Advances and Resources
A flexible MHC class I multimer loading system for large-scale detection of antigen-specific T cells
Luimstra et al. describe a temperature-mediated peptide exchange method for generating many different epitope-specific MHC class I multimers in parallel. This simple and versatile technology allows fast and efficient production of MHC I reagents for immune monitoring of T cell responses.