The Journal of Experimental Medicine This is an RSS file. You can use it to subscribe to this data in your favourite RSS reader or to display this data on your own website or blog.

Eran Elinav: Beyond the microbiome
Eran is the head of the microbiome-focused research group at the Weizmann Institute in Israel. He has published seminal work demonstrating the importance of the microbiota in many different systems, from post-dieting weight gain to circadian rhythms. Recent work from Eran and colleagues shows how probiotics perturb rather than aid the recovery of the microbiota following antibiotic treatment in humans. We contacted Eran to find out about his journey in science so far. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Houston, S. Tags: People & amp; Ideas Source Type: research

Neutrophil: A mobile fertilizer
In this issue of JEM, Lee et al. (https://doi.org/10.1084/jem.20181170) provide evidence to show that early influx of neutrophils into omentum represents a key mechanism in establishing the premetastatic niche for the subsequent implantation of ovarian cancer cells at this site. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Ng, L. G. Tags: Innate Immunity and Inflammation, Hematopoiesis Insights Source Type: research

Correction: Epidermal {gamma}{delta} T cells originate from yolk sac hematopoiesis and clonally self-renew in the adult
Vol. 215, No. 12, December 3, 2018. 10.1084/jem.20181206. JEM regrets that in the original version of this paper, the labels in Fig. 2, C and D, appeared incorrectly as a result of a production error.... (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Gentek, R., Ghigo, C., Hoeffel, G., Jorquera, A., Msallam, R., Wienert, S., Klauschen, F., Ginhoux, F., Bajenoff, M. Tags: Corrections Source Type: research

HDAC stimulates gene expression through BRD4 availability in response to IFN and in interferonopathies
In contrast to the common role of histone deacetylases (HDACs) for gene repression, HDAC activity provides a required positive function for IFN-stimulated gene (ISG) expression. Here, we show that HDAC1/2 as components of the Sin3A complex are required for ISG transcriptional elongation but not for recruitment of RNA polymerase or transcriptional initiation. Transcriptional arrest by HDAC inhibition coincides with failure to recruit the epigenetic reader Brd4 and elongation factor P-TEFb due to sequestration of Brd4 on hyperacetylated chromatin. Brd4 availability is regulated by an equilibrium cycle between opposed acetylt...
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Marie, I. J., Chang, H.-M., Levy, D. E. Tags: Autoimmunity, Innate Immunity and Inflammation, Infectious Disease and Host Defense Articles Source Type: research

The E3 ligase VHL controls alveolar macrophage function via metabolic-epigenetic regulation
Metabolic pathways such as glycolysis or oxidative phosphorylation play a key role in regulating macrophage function during inflammation and tissue repair. However, how exactly the VHL–HIF–glycolysis axis is involved in the function of tissue-resident macrophages remains unclear. Here we demonstrate that loss of VHL in myeloid cells resulted in attenuated pulmonary type 2 and fibrotic responses, accompanied by reduced eosinophil infiltration, decreased IL-5 and IL-13 concentrations, and ameliorated fiber deposition upon challenge. VHL deficiency uplifted glycolytic metabolism, decreased respiratory capacity, an...
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Zhang, W., Li, Q., Li, D., Li, J., Aki, D., Liu, Y.-C. Tags: Innate Immunity and Inflammation, Metabolism Articles Source Type: research

PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt
Phosphatidylinositol-3 kinases (PI3Ks) modulate cellular growth, proliferation, and survival; dysregulation of the PI3K pathway can lead to autoimmune disease and cancer. PIK3IP1 (or transmembrane inhibitor of PI3K [TrIP]) is a putative transmembrane regulator of PI3K. TrIP contains an extracellular kringle domain and an intracellular domain with homology to the inter-SH2 domain of the PI3K regulatory subunit p85, but the mechanism of TrIP function is poorly understood. We show that both the kringle and p85-like domains are necessary for TrIP inhibition of PI3K and that TrIP is down-modulated from the surface of T cells du...
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Uche, U. U., Piccirillo, A. R., Kataoka, S., Grebinoski, S. J., DCruz, L. M., Kane, L. P. Tags: Articles Source Type: research

Loss of human ICOSL results in combined immunodeficiency
We report a patient with combined immunodeficiency, marked by recurrent respiratory tract and DNA-based viral infections, hypogammaglobulinemia, and panlymphopenia. He also developed moderate neutropenia but without prototypical pyogenic infections. Using whole-exome sequencing, we identified a homozygous mutation in the inducible T cell costimulator ligand gene (ICOSLG; c.657C>G; p.N219K). Whereas WT ICOSL is expressed at the cell surface, the ICOSLN219K mutation abrogates surface localization: mutant protein is retained in the endoplasmic reticulum/Golgi apparatus, which is predicted to result from deleterious conform...
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Roussel, L., Landekic, M., Golizeh, M., Gavino, C., Zhong, M.-C., Chen, J., Faubert, D., Blanchet-Cohen, A., Dansereau, L., Parent, M.-A., Marin, S., Luo, J., Le, C., Ford, B. R., Langelier, M., King, I. L., Divangahi, M., Foulkes, W. D., Veillette, A., V Tags: Immunodeficiency, Human Disease Genetics Articles Source Type: research

CNBP controls IL-12 gene transcription and Th1 immunity
An inducible program of inflammatory gene expression is a hallmark of antimicrobial defenses. Recently, cellular nucleic acid–binding protein (CNBP) was identified as a regulator of nuclear factor-kappaB (NF-B)–dependent proinflammatory cytokine gene expression. Here, we generated mice lacking CNBP and found that CNBP regulates a very restricted gene signature that includes IL-12β. CNBP resides in the cytosol of macrophages and translocates to the nucleus in response to diverse microbial pathogens and pathogen-derived products. Cnbp-deficient macrophages induced canonical NF-B/Rel signaling normally but we...
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Chen, Y., Sharma, S., Assis, P. A., Jiang, Z., Elling, R., Olive, A. J., Hang, S., Bernier, J., Huh, J. R., Sassetti, C. M., Knipe, D. M., Gazzinelli, R. T., Fitzgerald, K. A. Tags: Innate Immunity and Inflammation Articles Source Type: research

Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities
Kras-driven non–small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the enzymatic subunit of polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice with orthotopic Kras-driven NSCLC grafts, which homogeneously express Ezh2. These tumors display sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program involving signaling through NF-B and genes residing in PRC2-regulated chromatin. During this process, tumor cells overcome GSK126 antiproliferative effects...
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Serresi, M., Siteur, B., Hulsman, D., Company, C., Schmitt, M. J., Lieftink, C., Morris, B., Cesaroni, M., Proost, N., Beijersbergen, R. L., van Lohuizen, M., Gargiulo, G. Tags: Solid Tumors, Innate Immunity and Inflammation Articles Source Type: research

PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia
The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondrial apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (EZH2, EED, or SUZ12) were associated with mitochondrial apoptosis r...
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Ariës, I. M., Bodaar, K., Karim, S. A., Chonghaile, T. N., Hinze, L., Burns, M. A., Pfirrmann, M., Degar, J., Landrigan, J. T., Balbach, S., Peirs, S., Menten, B., Isenhart, R., Stevenson, K. E., Neuberg, D. S., Devidas, M., Loh, M. L., Hunger, S. Tags: Leukemia & Lymphoma Articles Source Type: research

Bone marrow-derived fibroblasts are a functionally distinct stromal cell population in breast cancer
We report that bone marrow (BM)–derived mesenchymal stromal cells (MSCs) are recruited to primary breast tumors and to lung metastases and differentiate to a distinct subpopulation of CAFs. We show that BM-derived CAFs are functionally important for tumor growth and enhance angiogenesis via up-regulation of Clusterin. Using newly generated transgenic mice and adoptive BM transplantations, we demonstrate that BM-derived fibroblasts are a substantial source of CAFs in the tumor microenvironment. Unlike resident CAFs, BM-derived CAFs do not express PDGFRα, and their recruitment resulted in a decrease in the percen...
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Raz, Y., Cohen, N., Shani, O., Bell, R. E., Novitskiy, S. V., Abramovitz, L., Levy, C., Milyavsky, M., Leider-Trejo, L., Moses, H. L., Grisaru, D., Erez, N. Tags: Solid Tumors Articles Source Type: research

IFN{gamma}-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin
Mechanisms of immune suppression in peripheral tissues counteract protective immunity to prevent immunopathology and are coopted by tumors for immune evasion. While lymphatic vessels facilitate T cell priming, they also exert immune suppressive effects in lymph nodes at steady-state. Therefore, we hypothesized that peripheral lymphatic vessels acquire suppressive mechanisms to limit local effector CD8+ T cell accumulation in murine skin. We demonstrate that nonhematopoietic PD-L1 is largely expressed by lymphatic and blood endothelial cells and limits CD8+ T cell accumulation in tumor microenvironments. IFN produced by tis...
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Lane, R. S., Femel, J., Breazeale, A. P., Loo, C. P., Thibault, G., Kaempf, A., Mori, M., Tsujikawa, T., Chang, Y. H., Lund, A. W. Tags: Solid Tumors, Tumor Immunology Articles Source Type: research

Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies
SRPK2 is abnormally activated in tauopathies including Alzheimer’s disease (AD). SRPK2 is known to play an important role in pre–mRNA splicing by phosphorylating SR-splicing factors. Dysregulation of tau exon 10 pre–mRNA splicing causes pathological imbalances in 3R- and 4R-tau, leading to neurodegeneration; however, the role of SRPK2 in these processes remains unclear. Here we show that delta-secretase (also known as asparagine endopeptidase; AEP), which is activated in AD, cleaves SRPK2 and increases its nuclear translocation as well as kinase activity, augmenting exon 10 inclusion. Conversely, AEP-uncl...
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Wang, Z.-H., Liu, P., Liu, X., Yu, S. P., Wang, J.-Z., Ye, K. Tags: Neuroscience Articles Source Type: research

TLR8 and its endogenous ligand miR-21 contribute to neuropathic pain in murine DRG
Toll-like receptors (TLRs) are nucleic acid–sensing receptors and have been implicated in mediating pain and itch. Here we report that Tlr8–/– mice show normal itch behaviors, but have defects in neuropathic pain induced by spinal nerve ligation (SNL) in mice. SNL increased TLR8 expression in small-diameter IB4+ DRG neurons. Inhibition of TLR8 in the DRG attenuated SNL-induced pain hypersensitivity. Conversely, intrathecal or intradermal injection of TLR8 agonist, VTX-2337, induced TLR8-dependent pain hypersensitivity. Mechanistically, TLR8, localizing in the endosomes and lysosomes, mediated ERK activati...
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Zhang, Z.-J., Guo, J.-S., Li, S.-S., Wu, X.-B., Cao, D.-L., Jiang, B.-C., Jing, P.-B., Bai, X.-Q., Li, C.-H., Wu, Z.-H., Lu, Y., Gao, Y.-J. Tags: Neuroinflammation, Neuroscience Articles Source Type: research

Genetic models reveal origin, persistence and non-redundant functions of IL-17-producing {gamma}{delta} T cells
T cells are highly conserved in jawed vertebrates, suggesting an essential role in the immune system. However, T cell–deficient Tcrd–/– mice display surprisingly mild phenotypes. We hypothesized that the lack of T cells in constitutive Tcrd–/– mice is functionally compensated by other lymphocytes taking over genuine T cell functions. To test this, we generated a knock-in model for diphtheria toxin–mediated conditional T cell depletion. In contrast to IFN-–producing T cells, IL-17–producing T cells (T17 cells) recovered inefficiently after depletion, and their niches were fill...
Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Sandrock, I., Reinhardt, A., Ravens, S., Binz, C., Wilharm, A., Martins, J., Oberdörfer, L., Tan, L., Lienenklaus, S., Zhang, B., Naumann, R., Zhuang, Y., Krueger, A., Förster, R., Prinz, I. Tags: Articles Source Type: research