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Journal of Experimental Medicine

Cara L Croft, Pedro E Cruz, Daniel H Ryu, Carolina Ceballos-Diaz, Kevin H Strang, Brittany M Woody, Wen-Lang Lin, Michael Deture, Edgardo Rodríguez-Lebrón, Dennis W Dickson, Paramita Chakrabarty, Yona Levites, Benoit I Giasson, Todd E Golde
It has been challenging to produce ex vivo models of the inclusion pathologies that are hallmark pathologies of many neurodegenerative diseases. Using three-dimensional mouse brain slice cultures (BSCs), we have developed a paradigm that rapidly and robustly recapitulates mature neurofibrillary inclusion and Lewy body formation found in Alzheimer's and Parkinson's disease, respectively. This was achieved by transducing the BSCs with recombinant adeno-associated viruses (rAAVs) that express α-synuclein or variants of tau...
February 15, 2019: Journal of Experimental Medicine
Fabian Klein, Mladen Mitrovic, Julien Roux, Corinne Engdahl, Lilly von Muenchow, Llucia Alberti-Servera, Hans Jörg Fehling, Pawel Pelczar, Antonius Rolink, Panagiotis Tsapogas
T cell development is critically dependent on successful rearrangement of antigen-receptor chains. At the β-selection checkpoint, only cells with a functional rearrangement continue in development. However, how nonselected T cells proceed in their dead-end fate is not clear. We identified low CD27 expression to mark pre-T cells that have failed to rearrange their β-chain. Expression profiling and single-cell transcriptome clustering identified a developmental trajectory through β-selection and revealed specific expression of the transcription factor Duxbl at a stage of high recombination activity before β-selection...
February 14, 2019: Journal of Experimental Medicine
Adi F Gazdar, John D Minna
In this issue of JEM , Chen et al. ( describe a new approach for the transformation of human pluripotent embryonic stem cells (hESCs) into neuroendocrine (NE) tumors of the lung closely resembling human small cell lung cancer (SCLC). Another recent study uses a different method to transform fully differentiated normal human cells into high-grade NE tumors (Park et al. 2018. Science These approaches and their models provide important new resources for developing diagnostic, preventative, and therapeutic approaches for high-grade NE tumors...
February 13, 2019: Journal of Experimental Medicine
Stoyan Dimitrov, Tanja Lange, Cécile Gouttefangeas, Anja T R Jensen, Michael Szczepanski, Jannik Lehnnolz, Surjo Soekadar, Hans-Georg Rammensee, Jan Born, Luciana Besedovsky
Efficient T cell responses require the firm adhesion of T cells to their targets, e.g., virus-infected cells, which depends on T cell receptor (TCR)-mediated activation of β2 -integrins. Gαs -coupled receptor agonists are known to have immunosuppressive effects, but their impact on TCR-mediated integrin activation is unknown. Using multimers of peptide major histocompatibility complex molecules (pMHC) and of ICAM-1-the ligand of β2 -integrins-we show that the Gαs -coupled receptor agonists isoproterenol, epinephrine, norepinephrine, prostaglandin (PG) E2 , PGD2 , and adenosine strongly inhibit integrin activation on human CMV- and EBV-specific CD8+ T cells in a dose-dependent manner...
February 12, 2019: Journal of Experimental Medicine
Kyle Tretina, Eui-Soon Park, Agnieszka Maminska, John D MacMicking
Guanylate-binding proteins (GBPs) have recently emerged as central orchestrators of immunity to infection, inflammation, and neoplastic diseases. Within numerous host cell types, these IFN-induced GTPases assemble into large nanomachines that execute distinct host defense activities against a wide variety of microbial pathogens. In addition, GBPs customize inflammasome responses to bacterial infection and sepsis, where they act as critical rheostats to amplify innate immunity and regulate tissue damage. Similar functions are becoming evident for metabolic inflammatory syndromes and cancer, further underscoring the importance of GBPs within infectious as well as altered homeostatic settings...
February 12, 2019: Journal of Experimental Medicine
Isabel Barnstorf, Mariana Borsa, Nicolas Baumann, Katharina Pallmer, Alexander Yermanos, Nicole Joller, Roman Spörri, Suzanne P M Welten, Nike J Kräutler, Annette Oxenius
Chronic viral infections are widespread among humans, with ∼8-12 chronic viral infections per individual, and there is epidemiological proof that these impair heterologous immunity. We studied the impact of chronic LCMV infection on the phenotype and function of memory bystander CD8+ T cells. Active chronic LCMV infection had a profound effect on total numbers, phenotype, and function of memory bystander T cells in mice. The phenotypic changes included up-regulation of markers commonly associated with effector and exhausted cells and were induced by IL-6 in a STAT1-dependent manner in the context of chronic virus infection...
February 11, 2019: Journal of Experimental Medicine
Huanhuan Joyce Chen, Asaf Poran, Arun M Unni, Sarah Xuelian Huang, Olivier Elemento, Hans-Willem Snoeck, Harold Varmus
Cancer models based on cells derived from human embryonic stem cells (hESCs) may reveal why certain constellations of genetic changes drive carcinogenesis in specialized lineages. Here we demonstrate that inhibition of NOTCH signaling induces up to 10% of lung progenitor cells to form pulmonary neuroendocrine cells (PNECs), putative precursors to small cell lung cancers (SCLCs), and we can increase PNECs by reducing levels of retinoblastoma (RB) proteins with inhibitory RNA. Reducing levels of TP53 protein or expressing mutant KRAS or EGFR genes did not induce or expand PNECs, but tumors resembling early-stage SCLC grew in immunodeficient mice after subcutaneous injection of PNEC-containing cultures in which expression of both RB and TP53 was blocked...
February 8, 2019: Journal of Experimental Medicine
Jing Liu, Wenna Jiang, Kaili Zhao, Hongwei Wang, Tianxing Zhou, Weiwei Bai, Xiuchao Wang, Tiansuo Zhao, Chongbiao Huang, Song Gao, Tai Qin, Wenwen Yu, Bo Yang, Xin Li, Danqi Fu, Wei Tan, Shengyu Yang, He Ren, Jihui Hao
Pancreatic ductal adenocarcinoma (PDAC) is a highly immune-suppressive tumor with a low response rate to single checkpoint blockade therapy. ETS homologous factor (EHF) is a tumor suppressor in PDAC. Here, we report a novel function of EHF in pancreatic cancer immune microenvironment editing and efficacy prediction for anti-PD1 therapy. Our findings support that the deficiency of tumoral EHF induced the accumulation of regulatory T (T reg) cells and myeloid-derived suppressor cells (MDSCs) and a decrease in the number of tumor-infiltrating CD8+ T cells...
February 7, 2019: Journal of Experimental Medicine
Alessandro Malara, Cristian Gruppi, Vittorio Abbonante, Daniele Cattaneo, Luigi De Marco, Margherita Massa, Alessandra Iurlo, Umberto Gianelli, Carlo L Balduini, Maria E Tira, Andrès F Muro, Anil K Chauhan, Vittorio Rosti, Giovanni Barosi, Alessandra Balduini
The fibronectin EDA isoform (EDA FN) is instrumental in fibrogenesis but, to date, its expression and function in bone marrow (BM) fibrosis have not been explored. We found that mice constitutively expressing the EDA domain (EIIIA+/+ ), but not EDA knockout mice, are more prone to develop BM fibrosis upon treatment with the thrombopoietin (TPO) mimetic romiplostim (TPOhigh ). Mechanistically, EDA FN binds to TLR4 and sustains progenitor cell proliferation and megakaryopoiesis in a TPO-independent fashion, inducing LPS-like responses, such as NF-κB activation and release of profibrotic IL-6...
February 7, 2019: Journal of Experimental Medicine
R Grant Rowe, Edroaldo Lummertz da Rocha, Patricia Sousa, Pavlos Missios, Michael Morse, William Marion, Alena Yermalovich, Jessica Barragan, Ronald Mathieu, Deepak Kumar Jha, Mark D Fleming, Trista E North, George Q Daley
Leukemia phenotypes vary with age of onset. Delineating mechanisms of age specificity in leukemia could improve disease models and uncover new therapeutic approaches. Here, we used heterochronic transplantation of leukemia driven by MLL / KMT2A translocations to investigate the contribution of the age of the hematopoietic microenvironment to age-specific leukemia phenotypes. When driven by MLL-AF9 , leukemia cells in the adult microenvironment sustained a myeloid phenotype, whereas the neonatal microenvironment supported genesis of mixed early B cell/myeloid leukemia...
February 6, 2019: Journal of Experimental Medicine
Alice E Denton, Silvia Innocentin, Edward J Carr, Barry M Bradford, Fanny Lafouresse, Neil A Mabbott, Urs Mörbe, Burkhard Ludewig, Joanna R Groom, Kim L Good-Jacobson, Michelle A Linterman
Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context of infection, this response can be beneficial for the host: influenza A virus infection-induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite the ubiquity of ectopic lymphoid structures and their role in both health and disease, little is known about the mechanisms by which inflammation is able to convert a peripheral tissue into one that resembles a secondary lymphoid organ...
February 5, 2019: Journal of Experimental Medicine
Hans Schreiber
In this issue of JEM , Gao et al. ( demystify the exceptional metastatic success of ovarian cancer, the most lethal female malignancy: fibroblasts form heterotypic aggregates with disseminating cancer cells, thereby providing them with reciprocal signaling and matrix for adherence.
February 1, 2019: Journal of Experimental Medicine
Qinglei Gao, Zongyuan Yang, Sen Xu, Xiaoting Li, Xin Yang, Ping Jin, Yi Liu, Xiaoshui Zhou, Taoran Zhang, Cheng Gong, Xiao Wei, Dan Liu, Chaoyang Sun, Gang Chen, Junbo Hu, Li Meng, Jianfeng Zhou, Kenjiro Sawada, Robert Fruscio, Thomas W Grunt, Jörg Wischhusen, Víctor Manuel Vargas-Hernández, Bhavana Pothuri, Robert L Coleman
High-grade serous ovarian cancer (HGSOC) is hallmarked by early onset of peritoneal dissemination, which distinguishes it from low-grade serous ovarian cancer (LGSOC). Here, we describe the aggressive nature of HGSOC ascitic tumor cells (ATCs) characterized by integrin α5high (ITGA5high ) ATCs, which are prone to forming heterotypic spheroids with fibroblasts. We term these aggregates as metastatic units (MUs) in HGSOC for their advantageous metastatic capacity and active involvement in early peritoneal dissemination...
February 1, 2019: Journal of Experimental Medicine
Shenda Hou, Rachel L Clement, Alos Diallo, Bruce R Blazar, Alexander Y Rudensky, Arlene H Sharpe, Peter T Sage
Follicular regulatory T (Tfr) cells are a regulatory T cell subset that controls antibody production by inhibiting T follicular helper (Tfh)-mediated help to B cells. Tfh and Tfr cells possess opposing functions suggesting unique programming. Here we elucidated the transcriptional program controlling Tfr suppressive function. We found that Tfr cells have a program for suppressive function fine-tuned by tissue microenvironment. The transcription factor FoxP3 and chromatin-modifying enzyme EZH2 are essential for this transcriptional program but regulate the program in distinct ways...
January 31, 2019: Journal of Experimental Medicine
Rino Rappuoli, Giuseppe Del Giudice
Immunogens inducing antibodies against the stem of influenza virus hemagglutinin are promising candidates for the development of universal vaccines. In this issue of JEM , Kosik et al. ( report that inhibition of neuraminidase by anti-stem antibodies contributes to their broadly neutralizing activity.
January 25, 2019: Journal of Experimental Medicine
Ivan Kosik, Davide Angeletti, James S Gibbs, Matthew Angel, Kazuyo Takeda, Martina Kosikova, Vinod Nair, Heather D Hickman, Hang Xie, Christopher B Brooke, Jonathan W Yewdell
Broadly neutralizing antibodies (Abs) that bind the influenza virus hemagglutinin (HA) stem may enable universal influenza vaccination. Here, we show that anti-stem Abs sterically inhibit viral neuraminidase (NA) activity against large substrates, with activity inversely proportional to the length of the fibrous NA stalk that supports the enzymatic domain. By modulating NA stalk length in recombinant IAVs, we show that anti-stem Abs inhibit virus release from infected cells by blocking NA, accounting for their in vitro neutralization activity...
January 25, 2019: Journal of Experimental Medicine
Matthew L Hedberg, Noah D Peyser, Julie E Bauman, William E Gooding, Hua Li, Neil E Bhola, Tian Ran Zhu, Yan Zeng, Toni M Brand, Mi-Ok Kim, Richard C K Jordan, Scott VandenBerg, Victor Olivas, Trever G Bivona, Simion I Chiosea, Lin Wang, Gordon B Mills, Jonas T Johnson, Umamaheswar Duvvuri, Robert L Ferris, Patrick Ha, Daniel E Johnson, Jennifer R Grandis
PIK3CA is the most commonly altered oncogene in head and neck squamous cell carcinoma (HNSCC). We evaluated the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on survival in a PIK3CA -characterized cohort of 266 HNSCC patients and explored the mechanism in relevant preclinical models including patient-derived xenografts. Among subjects with PIK3CA mutations or amplification, regular NSAID use (≥6 mo) conferred markedly prolonged disease-specific survival (DSS; hazard ratio 0.23, P = 0.0032, 95% CI 0...
January 25, 2019: Journal of Experimental Medicine
Luis M Franco, Manasi Gadkari, Katherine N Howe, Jing Sun, Lela Kardava, Parag Kumar, Sangeeta Kumari, Zonghui Hu, Iain D C Fraser, Susan Moir, John S Tsang, Ronald N Germain
Glucocorticoids remain the most widely used immunosuppressive and anti-inflammatory drugs, yet substantial gaps exist in our understanding of glucocorticoid-mediated immunoregulation. To address this, we generated a pathway-level map of the transcriptional effects of glucocorticoids on nine primary human cell types. This analysis revealed that the response to glucocorticoids is highly cell type dependent, in terms of the individual genes and pathways affected, as well as the magnitude and direction of transcriptional regulation...
January 23, 2019: Journal of Experimental Medicine
Atsushi Anzai, John E Mindur, Lennard Halle, Soichi Sano, Jennifer L Choi, Shun He, Cameron S McAlpine, Christopher T Chan, Florian Kahles, Colin Valet, Ashley M Fenn, Manfred Nairz, Sara Rattik, Yoshiko Iwamoto, DeLisa Fairweather, Kenneth Walsh, Peter Libby, Matthias Nahrendorf, Filip K Swirski
Acquisition of self-reactive effector CD4+ T cells is a major component of the autoimmune response that can occur during myocarditis, an inflammatory form of cardiomyopathy. Although the processes by which self-reactive T cells gain effector function have received considerable attention, how these T cells contribute to effector organ inflammation and damage is less clear. Here, we identified an IL-3-dependent amplification loop that exacerbates autoimmune inflammation. In experimental myocarditis, we show that effector organ-accumulating autoreactive IL-3+ CD4+ T cells stimulate IL-3R+ tissue macrophages to produce monocyte-attracting chemokines...
January 22, 2019: Journal of Experimental Medicine
Caterina E Faliti, Roberta Gualtierotti, Elsa Rottoli, Maria Gerosa, Lisa Perruzza, Andrea Romagnani, Giovanni Pellegrini, Benedetta De Ponte Conti, Riccardo L Rossi, Marco Idzko, Emilia M C Mazza, Silvio Bicciato, Elisabetta Traggiai, Pier Luigi Meroni, Fabio Grassi
Altered control of T follicular helper (Tfh) cells can lead to generation of autoantibodies and autoimmune manifestations. Signaling pathways that selectively limit pathogenic responses without affecting the protective function of Tfh cells are unknown. Here we show that the ATP-gated ionotropic P2X7 receptor restricts the expansion of aberrant Tfh cells and the generation of self-reactive antibodies in experimental murine lupus, but its activity is dispensable for the expansion of antigen-specific Tfh cells during vaccination...
January 17, 2019: Journal of Experimental Medicine
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