Issues

We are excited to introduce a new design for JEM.

In this issue of JEM, Antila et al. demonstrate that central nervous system lymphatics develop in the mouse meninges during early postnatal periods and display remarkable plasticity in adult periods through manipulation of VEGF-C–VEGFR3 signaling.

In this issue of JEM, Swanson et al. report an unanticipated role for cGAMP in priming and activation of inflammasomes in addition to its well-characterized function as an endogenous second messenger inducing type I interferons in the cytosolic DNA-sensing pathway.

In this issue of JEM, Wang et al. show a novel antiviral innate mechanism by which methyltransferase NSD3 directly monomethylates a transcription factor IRF3 and maintains IRF3 phosphorylation to enhance its transcriptional activity, consequently promoting antiviral innate immune responses.

In this issue of JEM, Krejciova et al. report that astrocytes derived from human iPSCs can replicate human CJD prions. These observations provide a new, potentially very valuable model for studying human prions in cellula and for identifying antiprion compounds that might serve as clinical candidates. Furthermore, they add to the evidence that astrocytes may not be just innocent bystanders in prion diseases.

Krejciova et al. present the first study demonstrating that CJD prions infect human stem cell–derived astrocytes in vitro. This provides a physiologically relevant model for discovery of key molecular pathogenic events of CJD and facilitates the development of future therapies.

Pierce et al. describe a pediatric patient with a fatal systemic capillary leak syndrome (Clarkson’s disease). They identify a point mutation in p190BRhoGAP and show that patient-derived microvascular endothelial cells show prolonged activation RhoB that correlates with impaired barrier recovery after treatment with TNF compared with control cultures.

Hayase et al. show that R-Spondin1 stimulates intestinal stem cells to differentiate to Paneth cells and enhances luminal secretion of α-defensins. Administration of R-Spondin1 or recombinant α-defensin prevents dysbiosis mediated by graft-versus-host disease, representing a novel approach to restore intestinal ecosystems and homeostasis.

Kasheta et al. report the identification of T reg–like cells in zebrafish, a means to track and live-image these cells, and foxp3a-deficient mutants that display lymphoproliferation, severe inflammation, and other hallmarks of T reg deficiency syndromes.

Quatrini et al. demonstrate that neuroendocrine regulation of IFN-γ production by group 1 innate lymphoid cells (ILCs) is required to develop an IL-10–dependent resistance to endotoxin-induced septic shock, revealing a novel strategy of host protection from immunopathology.

The molecular mechanisms that regulate AID mutator activity at off-target genes are not well characterized. Mu et al. show AID phosphorylation dynamically controls activity at Myc and other sites. Pharmacological induction of AID phosphorylation leads to increased mutations, double strand breakss and translocations.

TBK1 is a critical kinase required for the induction of type I IFNs and subsequent cellular antiviral responses. Yu et al. show that USP1–UAF1 deubiquitinase complex removes K48-linked polyubiquitination of TBK1, stabilizes its expression, and thus enhances antiviral responses.

Green et al. find that T cell–derived amphiregulin facilitates lung tumor progression seemingly independently of the immune response, suggesting that T cells can promote tumor growth through the production of factors normally associated with tissue repair.

Ramadan et al. demonstrate that triggering the ST2–IL-33 pathway in IL-9–secreting T cells decreases the severity of graft-versus-host disease through AREG upregulation while maintaining graft versus leukemia activity by preserving the central memory phenotype of CD8, increasing CD8α and cytolytic molecule expression.

Wang et al. demonstrate that methyltransferase NSD3 directly methylates IRF3 and maintains IRF3 phosphorylation to enhance its transcriptional activity by disassociating the methylated IRF3 and PP1cc to prevent IRF3 dephosphorylation, consequently promoting antiviral innate immune response.

IFN-I signaling and inflammasome activation are two innate pathways important for combatting a variety of pathogens. Swanson et al. show that cGAMP activates the inflammasome in addition to IFN-I, and that the activation of both is needed to control infection by a DNA virus.

Singh et al. examined microRNA expression and physiological requirements in type 2 innate lymphoid cells (ILC2s). The miR-17∼92 cluster promotes ILC2 growth, cytokine expression, and function in allergic inflammation.

Antila et al. show that meningeal lymphatic vessels in mice develop postnatally. Interruption of VEGF-C/VEGFR3 signal transduction arrests their development. In adult mice, VEGFR3 deletion and VEGFR3 blockers, including a clinically available tyrosine kinase inhibitor, induce regression of meningeal lymphatic vessels.

Huang et al. show that the Alzheimer’s disease (AD) risk factor SORLA inhibits amyloid β–induced synaptotoxicity and cognitive impairment through interacting with and subsequently inactivating EphA4. These findings provide a novel mechanism by which the SORLA loss-of-function mutation significantly increases AD risk.

Matsuzawa-Ishimoto et al. show that autophagy gene ATG16L1, which is associated with inflammatory diseases of the gastrointestinal tract, is essential for preventing necroptotic cell death and loss of Paneth cells in the intestinal epithelium.

Rujano et al. report mutations in ATP6AP2 leading to liver disease, immunodeficiency, and psychomotor impairment. ATP6AP2 deficiency impairs the assembly and function of the V-ATPase proton pump, causing defects in protein glycosylation and autophagy.

Through transcriptional profiling of the mouse AGM region, McGarvey et al. identify potential niche regulators of HSC development. They show a new function of BMPER in regulating HSC maturation, likely via its modulation of BMP signalling.

Tsai et al. demonstrate that loss of Bim (BCL2L11) in myeloid cells in mice (LysM^CreBim^fl/fl) is sufficient to induce systemic autoimmunity. Kidney macrophages in LysM^CreBim^fl/fl mice possess a proinflammatory transcriptional signature and signal through TRIF to cause end-stage glomerulonephritis.

Veselits et al. show that Igβ ubiquitination activates PI3K and the accumulation of PIP₃ on BCR-associated endosomal membranes, which is necessary and sufficient for sorting into classical antigen-processing compartments. Surprisingly, proper BCR sorting is critical for endosomal TLR activation yet dispensable for T-dependent humoral immunity.

Dudeck et al. demonstrate that inflammatory conditions induce dynamic interactions between mast cells (MCs) and dendritic cells (DCs) culminating in protein exchange. Resident MCs are equipped with DC MHCII and empowered to initiate T cell–driven inflammation during migration-based DC absence.