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    ON THE COVER
    White et al. describe a new mechanism of thymus emigration that is controlled by expression of the type 2 IL-4 receptor by thymic stroma and production of IL-4 and IL-13 by thymic-resident invariant NKT cells. The cover shows an Il4ra−/− mouse thymus stained for CD4 (blue), CD8 (green), and the medullary epithelial cell marker ERTR5 (red), highlighting an epithelial-free area within the thymic medulla. The image was provided by the authors.
    See page 2205

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ISSN 0022-1007
EISSN 1540-9538

Editorial

Changes in the JEM Advisory Editorial Board.

Insights

In this issue of JEM, Marciniak et al. identify a putative novel function of tau protein as a regulator of insulin signaling in the brain. They find that tau deletion impairs hippocampal response to insulin through IRS-1 and PTEN dysregulation and suggest that, in Alzheimer's disease (AD), impairment of brain insulin signaling might occur via tau loss of function.

Review

In the Kunkel Society Lecture, Nathan calls “fundamental immunodeficiency” the inability of the encoded immune system to protect us from every life-threatening infection. The remedy is “adopted immunity,” including antimicrobial agents. Immunologists can engage with drug developers to help overcome the rising problem of antimicrobial resistance.

Despite the lack of nuclei and regulated transcription, platelets actively participate in multiple physiological processes, including hemostasis and immunity. Li et al. discuss aspects of platelet design that optimize its functions and argue that platelets may be best conceived as automated, fully equipped surveillance vehicles.

Brief Definitive Report

White et al. describe a new mechanism of thymus emigration that is controlled by expression of the type 2 IL-4 receptor by thymic stroma and production of IL-4 and IL-13 by thymic-resident invariant NKT cells.

The activation mechanism of ZBP1/DAI to regulate virus-induced programmed cell death is not known. Kesavardhana et al. show that ZBP1 senses viral ribonucleoproteins to induce cell death upon influenza A virus infection. Apical activation of RIG-I–IFNAR signaling to upregulate ZBP1 and influenza-induced ZBP1 ubiquitination are critical events for ZBP1 activation.

Alloatti et al. show that Sec22b-dependent antigen cross-presentation is critical to developing effective antitumor CD8+ T cell responses. Conditional deletion of Sec22b in dendritic cells decreases immune response against dead cells and promotes resistance to immunotherapy with anti–PD-1.

Rashidian et al. show that 89Zr-PEGylated single-domain antibodies that target CD8+ T cells can be used to monitor and evaluate the response to immunotherapy as a predictive tool.

Physiological functions of tau remain ill defined. In the present study, Marciniak et al. uncover a novel function of tau in its ability to regulate brain insulin signaling and discuss the pathophysiological implications of these findings for Alzheimer’s disease and tauopathies.

Machuca-Parra et al. show that restoring Notch3 signaling via genetic rescue in a Notch3 knockout or using a Notch3 agonist antibody in a mouse model of CADASIL can prevent small vessel disease.

Article

Schroeder et al. demonstrate that when peripheral tolerance is relaxed, tier 2 HIV-1–neutralizing antibodies can be elicited and identify new autoreactive antibody specificities against histone H2A capable of neutralizing tier 2 HIV-1.

Cao et al. report a new mechanism by which Zika virus maternal-fetal transmission may occur and be limited as autophagy inhibition protects mice from vertical viral transmission. This study suggests that an autophagy-based therapeutic intervention against ZIKV may be warranted.

Peng et al. show that human recurrent HSV-2 infection promotes peripheral nerve growth possibly through interactions between IL-17c production by keratinocytes and IL-17RE receptor expression on nerve fibers and sensory neurons. These findings explain the lack of nerve damage during HSV-2 recurrence.

Nussbaum et al. found that tumor suppression through innate lymphoid cells (ILCs) cannot be predicted solely based on the ILC phenotype and lineage but that their immune properties are shaped both by their ontogeny and by the tissue microenvironment they reside in.

Activation of cancer-associated fibroblasts (CAFs) promotes tumorigenesis. Kim et al. show that ATF3 and CSL converge in negative regulation of CAF activation through long-distance chromatin control. Bromodomain and extra-terminal (BET) inhibitors counteract the effects of ATF3 and CSL loss in CAF activation and cancer–stromal cell expansion.

Ferris et al. show that macrophages in pancreatic islets express a gene signature of activation consistent with barrier macrophages. Macrophages are poised to react to blood inflammatory stimuli. In NOD mice, an additional immune activation signature is observed as early as 3 wk of age.

Misharin et al. elucidate the fate and function of monocyte-derived alveolar macrophages during the course of pulmonary fibrosis. These cells persisted throughout the life span, were enriched for the expression of profibrotic genes, and their genetic ablation ameliorated development of pulmonary fibrosis.

NLRX1 is a mitochondrial innate immune receptor involved in viral immunity. Stokman et al. found that loss of NLRX1 increased cellular mitochondrial activity, production of reactive oxygen species, and apoptosis during oxidative stress in kidney injury.

Golec et al. show that RasGRP1, a critical Ras activator in thymocytes, is required for TCRαβ+CD8αα IEL development by regulating the survival of a heterogeneous population of thymic progenitors that receive a strong TCR signal. Therefore, RasGRP1 is necessary for thymic selection events stemming from strong or weak TCR signals.

Patients with mutations in FOXC2 and GJC2 have reduced venous valve number and leaflet length. Experiments in mice by Lyons et al. show that Foxc2-Calcineurin-Nfatc1, and Gja4, Gjc2, Gja1 regulate valve-forming cell organization. Foxc2, Calcineurin-Nfatc1, and blood flow regulate leaflet growth/maturation.

The mechanisms that regulate self-renewal in hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) are poorly understood. Herein, Khalaj et al. identify microRNA-99 (miR-99) as a novel noncoding RNA critical for the maintenance of HSCs and LSCs and demonstrate that miR-99 mediates its role by suppressing multiple target genes, including HOXA1.

Technical Advances and Resources

Sanjuan Nandin et al. describe an innovative approach based on antigen-dependent activation of human memory B cells in culture. It results in the rapid generation of human antibodies against infectious agents and offers the potential for therapeutic antibody production and vaccine development.

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