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.

Type I interferon induces CXCL13 to support ectopic germinal center formation
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 lymph...
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Denton, A. E., Innocentin, S., Carr, E. J., Bradford, B. M., Lafouresse, F., Mabbott, N. A., Mörbe, U., Ludewig, B., Groom, J. R., Good-Jacobson, K. L., Linterman, M. A. Tags: Infectious Disease and Host Defense, Mucosal Immunology Articles Source Type: research

FoxP3 and Ezh2 regulate Tfr cell suppressive function and transcriptional program
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. FoxP3 modifies the Tfh program to in...
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Hou, S., Clement, R. L., Diallo, A., Blazar, B. R., Rudensky, A. Y., Sharpe, A. H., Sage, P. T. Tags: Autoimmunity, Infectious Disease and Host Defense Articles Source Type: research

EDA fibronectin-TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis
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-B activation and release of profibrotic IL-6. Pharmacological inhibition of TLR4 ...
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Malara, A., Gruppi, C., Abbonante, V., Cattaneo, D., De Marco, L., Massa, M., Iurlo, A., Gianelli, U., Balduini, C. L., Tira, M. E., Muro, A. F., Chauhan, A. K., Rosti, V., Barosi, G., Balduini, A. Tags: Hematopoiesis Articles Source Type: research

Chronic virus infection compromises memory bystander T cell function in an IL-6/STAT1-dependent manner
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 inf...
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Barnstorf, I., Borsa, M., Baumann, N., Pallmer, K., Yermanos, A., Joller, N., Spörri, R., Welten, S. P. M., Kräutler, N. J., Oxenius, A. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense Articles Source Type: research

A major role for ferroptosis in Mycobacterium tuberculosis-induced cell death and tissue necrosis
Necrotic cell death during Mycobacterium tuberculosis (Mtb) infection is considered host detrimental since it facilitates mycobacterial spread. Ferroptosis is a type of regulated necrosis induced by accumulation of free iron and toxic lipid peroxides. We observed that Mtb-induced macrophage necrosis is associated with reduced levels of glutathione and glutathione peroxidase-4 (Gpx4), along with increased free iron, mitochondrial superoxide, and lipid peroxidation, all of which are important hallmarks of ferroptosis. Moreover, necrotic cell death in Mtb-infected macrophage cultures was suppressed by ferrostatin-1 (Fer-1), a...
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Amaral, E. P., Costa, D. L., Namasivayam, S., Riteau, N., Kamenyeva, O., Mittereder, L., Mayer-Barber, K. D., Andrade, B. B., Sher, A. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense Articles Source Type: research

The developmental stage of the hematopoietic niche regulates lineage in MLL-rearranged leukemia
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. In MLL-ENL leukemia, the neonatal microenvironment potenti...
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Rowe, R. G., Lummertz da Rocha, E., Sousa, P., Missios, P., Morse, M., Marion, W., Yermalovich, A., Barragan, J., Mathieu, R., Jha, D. K., Fleming, M. D., North, T. E., Daley, G. Q. Tags: Leukemia & Lymphoma, Hematopoiesis Brief Definitive Reports Source Type: research

G{alpha}s-coupled receptor signaling and sleep regulate integrin activation of human antigen-specific T cells
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 inh...
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Dimitrov, S., Lange, T., Gouttefangeas, C., Jensen, A. T. R., Szczepanski, M., Lehnnolz, J., Soekadar, S., Rammensee, H.-G., Born, J., Besedovsky, L. Tags: Infectious Disease and Host Defense, Neuroscience Brief Definitive Reports Source Type: research

Reactive species and pathogen antioxidant networks during phagocytosis
The generation of phagosomal cytotoxic reactive species (i.e., free radicals and oxidants) by activated macrophages and neutrophils is a crucial process for the control of intracellular pathogens. The chemical nature of these species, the reactions they are involved in, and the subsequent effects are multifaceted and depend on several host- and pathogen-derived factors that influence their production rates and catabolism inside the phagosome. Pathogens rely on an intricate and synergistic antioxidant armamentarium that ensures their own survival by detoxifying reactive species. In this review, we discuss the generation, ki...
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Piacenza, L., Trujillo, M., Radi, R. Tags: Infectious Disease and Host Defense Review Source Type: research

Interferon-induced guanylate-binding proteins: Guardians of host defense in health and disease
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 importan...
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Tretina, K., Park, E.-S., Maminska, A., MacMicking, J. D. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense Review Source Type: research

Claudia Jakubzick: Work hard, play hard
Claudia Jakubzick will be an Associate Professor at Dartmouth in the Department of Microbiology and Immunology working on immune homeostasis and how the immune system can recognize and target precancerous cells. She started her own laboratory at National Jewish Health in 2014, becoming a tenure-track Assistant Professor and an Associate Professor in 2017, and will relocate to Dartmouth mid-2019. She is also a member of the American Association of Immunologists’ Minority Affairs Committee. We contacted Claudia to find out about her career in science. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Houston, S. Tags: People & amp; Ideas Source Type: research

Fibroblasts: Dangerous travel companions
In this issue of JEM, Gao et al. (https://doi.org/10.1084/jem.20180765) 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. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Schreiber, H. Tags: Solid Tumors, Tumor Immunology Insights Source Type: research

Small cell lung cancers made from scratch
In this issue of JEM, Chen et al. (https://doi.org/10.1084/jem.20181155) 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. https://doi.org/10.1126/science.aat5749). These approaches and their models provide important new resources for developing diagnostic, preventative, and therapeutic approaches for high-grade NE tumors. (Sourc...
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Gazdar, A. F., Minna, J. D. Tags: Insights Source Type: research

Stand by me(mory): Chronic infection diminishes memory pool via IL-6/STAT1
Despite great efforts to eradicate chronic viral infections, they still remain a global health problem. In this issue, Barnstorf et al. (2019. J. Exp. Med. https://doi.org/10.1084/jem.20181589) show that virus-unspecific bystander memory T cells are highly affected during chronic viral infection via IL-6/STAT1. Bystander memory T cells are strongly decimated in numbers and change in phenotype and function during chronic viral infection. These data provide new explanations for immune-mediated problems during chronic virus infections. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Lang, P. A., Lang, K. S. Tags: Infectious Disease and Host Defense Insights Source Type: research

Die another way: Ferroptosis drives tuberculosis pathology
In this issue of JEM, Amaral et al. (https://doi.org/10.1084/jem.20181776) provide the first evidence that ferroptosis, a newly described form of regulated cell death, is detrimental for the host during a Mycobacterium tuberculosis infection. This finding has important implications for the development of host-directed therapies for tuberculosis. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - March 3, 2019 Category: Internal Medicine Authors: Meunier, E., Neyrolles, O. Tags: Infectious Disease and Host Defense Insights Source Type: research

LUBAC determines chemotherapy resistance in squamous cell lung cancer
Lung squamous cell carcinoma (LSCC) and adenocarcinoma (LADC) are the most common lung cancer subtypes. Molecular targeted treatments have improved LADC patient survival but are largely ineffective in LSCC. The tumor suppressor FBW7 is commonly mutated or down-regulated in human LSCC, and oncogenic KRasG12D activation combined with Fbxw7 inactivation in mice (KF model) caused both LSCC and LADC. Lineage-tracing experiments showed that CC10+, but not basal, cells are the cells of origin of LSCC in KF mice. KF LSCC tumors recapitulated human LSCC resistance to cisplatin-based chemotherapy, and we identified LUBAC-mediated NF...
Source: The Journal of Experimental Medicine - February 4, 2019 Category: Internal Medicine Authors: Ruiz, E. J., Diefenbacher, M. E., Nelson, J. K., Sancho, R., Pucci, F., Chakraborty, A., Moreno, P., Annibaldi, A., Liccardi, G., Encheva, V., Mitter, R., Rosenfeldt, M., Snijders, A. P., Meier, P., Calzado, M. A., Behrens, A. Tags: Solid Tumors Articles Source Type: research