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Journal of Experimental Medicine

Yang Zhang, Laura Tech, Laura A George, Andreas Acs, Russell E Durrett, Henry Hess, Lucy S K Walker, David M Tarlinton, Anne L Fletcher, Anja Erika Hauser, Kai-Michael Toellner
Germinal centers (GCs) are the sites where B cells undergo affinity maturation. The regulation of cellular output from the GC is not well understood. Here, we show that from the earliest stages of the GC response, plasmablasts emerge at the GC-T zone interface (GTI). We define two main factors that regulate this process: Tfh-derived IL-21, which supports production of plasmablasts from the GC, and TNFSF13 (APRIL), which is produced by a population of podoplanin+ CD157high fibroblastic reticular cells located in the GTI that are also rich in message for IL-6 and chemokines CXCL12, CCL19, and CCL21...
March 16, 2018: Journal of Experimental Medicine
Jonathan J Lyons, Joshua D Milner
Monogenic disorders have provided fundamental insights into human immunity and the pathogenesis of allergic diseases. The pathways identified as critical in the development of atopy range from focal defects in immune cells and epithelial barrier function to global changes in metabolism. A major goal of studying heritable single-gene disorders that lead to severe clinical allergic diseases is to identify fundamental pathways leading to hypersensitivity that can be targeted to provide novel therapeutic strategies for patients with allergic diseases, syndromic and nonsyndromic alike...
March 16, 2018: Journal of Experimental Medicine
Chun Wang, Susan Hockerman, E Jon Jacobsen, Yael Alippe, Shaun R Selness, Heidi R Hope, Jeffrey L Hirsch, Stephen J Mnich, Matthew J Saabye, William F Hood, Sheri L Bonar, Yousef Abu-Amer, Ariela Haimovich, Hal M Hoffman, Joseph B Monahan, Gabriel Mbalaviele
p38α activation of multiple effectors may underlie the failure of global p38α inhibitors in clinical trials. A unique inhibitor (CDD-450) was developed that selectively blocked p38α activation of the proinflammatory kinase MK2 while sparing p38α activation of PRAK and ATF2. Next, the hypothesis that the p38α-MK2 complex mediates inflammasome priming cues was tested. CDD-450 had no effect on NLRP3 expression, but it decreased IL-1β expression by promoting IL-1β mRNA degradation. Thus, IL-1β is regulated not only transcriptionally by NF-κB and posttranslationally by the inflammasomes but also posttranscriptionally by p38α-MK2...
March 16, 2018: Journal of Experimental Medicine
Marc-Werner Dobenecker, Joon Seok Park, Jonas Marcello, Michael T McCabe, Richard Gregory, Steven D Knight, Inmaculada Rioja, Anna K Bassil, Rabinder K Prinjha, Alexander Tarakhovsky
Differentiation and activation of T cells require the activity of numerous histone lysine methyltransferases (HMT) that control the transcriptional T cell output. One of the most potent regulators of T cell differentiation is the HMT Ezh2. Ezh2 is a key enzymatic component of polycomb repressive complex 2 (PRC2), which silences gene expression by histone H3 di/tri-methylation at lysine 27. Surprisingly, in many cell types, including T cells, Ezh2 is localized in both the nucleus and the cytosol. Here we show the presence of a nuclear-like PRC2 complex in T cell cytosol and demonstrate a role of cytosolic PRC2 in T cell antigen receptor (TCR)-mediated signaling...
March 9, 2018: Journal of Experimental Medicine
Difeng Fang, Kairong Cui, Gangqing Hu, Rama Krishna Gurram, Chao Zhong, Andrew J Oler, Ryoji Yagi, Ming Zhao, Suveena Sharma, Pentao Liu, Bing Sun, Keji Zhao, Jinfang Zhu
GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. However, it is still elusive how GATA3 function is precisely regulated in Th2 cells. Here, we show that the transcription factor B cell lymphoma 11b (Bcl11b), a previously unknown component of GATA3 transcriptional complex, is involved in GATA3-mediated gene regulation. Bcl11b binds to GATA3 through protein-protein interaction, and they colocalize at many important cis-regulatory elements in Th2 cells...
March 7, 2018: Journal of Experimental Medicine
Tal Teitz, Jie Fang, Asli N Goktug, Justine D Bonga, Shiyong Diao, Robert A Hazlitt, Luigi Iconaru, Marie Morfouace, Duane Currier, Yinmei Zhou, Robyn A Umans, Michael R Taylor, Cheng Cheng, Jaeki Min, Burgess Freeman, Junmin Peng, Martine F Roussel, Richard Kriwacki, R Kiplin Guy, Taosheng Chen, Jian Zuo
Hearing loss caused by aging, noise, cisplatin toxicity, or other insults affects 360 million people worldwide, but there are no Food and Drug Administration-approved drugs to prevent or treat it. We screened 4,385 small molecules in a cochlear cell line and identified 10 compounds that protected against cisplatin toxicity in mouse cochlear explants. Among them, kenpaullone, an inhibitor of multiple kinases, including cyclin-dependent kinase 2 (CDK2), protected zebrafish lateral-line neuromasts from cisplatin toxicity and, when delivered locally, protected adult mice and rats against cisplatin- and noise-induced hearing loss...
March 7, 2018: Journal of Experimental Medicine
Ashley V Menk, Nicole E Scharping, Dayana B Rivadeneira, Michael J Calderon, McLane J Watson, Deanna Dunstane, Simon C Watkins, Greg M Delgoffe
Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to these therapies. The tumor microenvironment can impose metabolic restrictions on T cell function, creating a resistance mechanism to immunotherapy. We have previously shown tumor-infiltrating T cells succumb to progressive loss of metabolic sufficiency, characterized by repression of mitochondrial activity that cannot be rescued by PD-1 blockade. 4-1BB, a costimulatory molecule highly expressed on exhausted T cells, has been shown to influence metabolic function...
March 6, 2018: Journal of Experimental Medicine
Anna Baranska, Alaa Shawket, Mabel Jouve, Myriam Baratin, Camille Malosse, Odessa Voluzan, Thien-Phong Vu Manh, Frédéric Fiore, Marc Bajénoff, Philippe Benaroch, Marc Dalod, Marie Malissen, Sandrine Henri, Bernard Malissen
Here we describe a new mouse model that exploits the pattern of expression of the high-affinity IgG receptor (CD64) and allows diphtheria toxin (DT)-mediated ablation of tissue-resident macrophages and monocyte-derived cells. We found that the myeloid cells of the ear skin dermis are dominated by DT-sensitive, melanin-laden cells that have been missed in previous studies and correspond to macrophages that have ingested melanosomes from neighboring melanocytes. Those cells have been referred to as melanophages in humans...
March 6, 2018: Journal of Experimental Medicine
Na Li, Vincent van Unen, Thomas Höllt, Allan Thompson, Jeroen van Bergen, Nicola Pezzotti, Elmar Eisemann, Anna Vilanova, Susana M Chuva de Sousa Lopes, Boudewijn P F Lelieveldt, Frits Koning
Innate lymphoid cells (ILCs) are abundant in mucosal tissues and involved in tissue homeostasis and barrier function. Although several ILC subsets have been identified, it is unknown if additional heterogeneity exists, and their differentiation pathways remain largely unclear. We applied mass cytometry to analyze ILCs in the human fetal intestine and distinguished 34 distinct clusters through a t-SNE-based analysis. A lineage (Lin)- CD7+ CD127- CD45RO+ CD56+ population clustered between the CD127+ ILC and natural killer (NK) cell subsets, and expressed diverse levels of Eomes, T-bet, GATA3, and RORγt...
March 6, 2018: Journal of Experimental Medicine
Sharmila Nair, Jeremy P Huynh, Vicky Lampropoulou, Ekaterina Loginicheva, Ekaterina Esaulova, Anshu P Gounder, Adrianus C M Boon, Elizabeth A Schwarzkopf, Tara R Bradstreet, Brian T Edelson, Maxim N Artyomov, Christina L Stallings, Michael S Diamond
Immune-Responsive Gene 1 (Irg1) is a mitochondrial enzyme that produces itaconate under inflammatory conditions, principally in cells of myeloid lineage. Cell culture studies suggest that itaconate regulates inflammation through its inhibitory effects on cytokine and reactive oxygen species production. To evaluate the functions of Irg1 in vivo, we challenged wild-type (WT) and Irg1 -/- mice with Mycobacterium tuberculosis ( Mtb ) and monitored disease progression. Irg1 -/- , but not WT, mice succumbed rapidly to Mtb , and mortality was associated with increased infection, inflammation, and pathology...
March 6, 2018: Journal of Experimental Medicine
Matthew Stephen Mangan, Eicke Latz
In this issue of JEM, Malireddi et al. ( demonstrate that macrophage-specific loss of TAK1 causes spontaneous NLRP3 inflammasome activation, driven by unregulated TNF secretion and signaling. This has implications for therapeutically targeting TAK1, enhancing its potential function as an anticancer drug treatment.
March 5, 2018: Journal of Experimental Medicine
Lu Huang, Evgeniya V Nazarova, Shumin Tan, Yancheng Liu, David G Russell
To understand how infection by Mycobacterium tuberculosis (Mtb) is modulated by host cell phenotype, we characterized those host phagocytes that controlled or supported bacterial growth during early infection, focusing on the ontologically distinct alveolar macrophage (AM) and interstitial macrophage (IM) lineages. Using fluorescent Mtb reporter strains, we found that bacilli in AM exhibited lower stress and higher bacterial replication than those in IM. Interestingly, depletion of AM reduced bacterial burden, whereas depletion of IM increased bacterial burden...
March 2, 2018: Journal of Experimental Medicine
R K Subbarao Malireddi, Prajwal Gurung, Jayadev Mavuluri, Tejasvi Krishna Dasari, Jeffery M Klco, Hongbo Chi, Thirumala-Devi Kanneganti
The NOD-like receptor (NLR)-P3 inflammasome is a global sensor of infection and stress. Elevated NLRP3 activation levels are associated with human diseases, but the mechanisms controlling NLRP3 inflammasome activation are largely unknown. Here, we show that TGF-β activated kinase-1 (TAK1) is a central regulator of NLRP3 inflammasome activation and spontaneous cell death. Absence of TAK1 in macrophages induced spontaneous activation of the NLRP3 inflammasome without requiring toll-like receptor (TLR) priming and subsequent activating signals, suggesting a distinctive role for TAK1 in maintaining NLRP3 inflammasome homeostasis...
March 2, 2018: Journal of Experimental Medicine
Anthony J St Leger, Anna M Hansen, Hatice Karauzum, Reiko Horai, Cheng-Rong Yu, Arian Laurence, Katrin D Mayer-Barber, Phyllis Silver, Rafael Villasmil, Charles Egwuagu, Sandip K Datta, Rachel R Caspi
Appropriate regulation of IL-17 production in the host can mean the difference between effective control of pathogens and uncontrolled inflammation that causes tissue damage. Investigation of conventional CD4+ T cells (Th17 cells) has yielded invaluable insights into IL-17 function and its regulation. More recently, we and others reported production of IL-17 from innate αβ+ T cell populations, which was shown to occur primarily via IL-23R signaling through the transcription factor STAT-3. In our current study, we identify promyelocytic leukemia zinc finger (PLZF)-expressing iNKT, CD4- /CD8+ , and CD4- /CD8- (DN) αβ+T cells, which produce IL-17 in response to TCR and IL-1 receptor ligation independently of STAT-3 signaling...
February 28, 2018: Journal of Experimental Medicine
Dan Xu, Andrew P Robinson, Toshiyuki Ishii, D'Anne S Duncan, Tord D Alden, Gwendolyn E Goings, Igal Ifergan, Joseph R Podojil, Pablo Penaloza-MacMaster, Jennifer A Kearney, Geoffrey T Swanson, Stephen D Miller, Sookyong Koh
The pathophysiology of drug-resistant pediatric epilepsy is unknown. Flow cytometric analysis of inflammatory leukocytes in resected brain tissues from 29 pediatric patients with genetic (focal cortical dysplasia) or acquired (encephalomalacia) epilepsy demonstrated significant brain infiltration of blood-borne inflammatory myeloid cells and memory CD4+ and CD8+ T cells. Significantly, proinflammatory (IL-17- and GM-CSF-producing) γδ T cells were concentrated in epileptogenic lesions, and their numbers positively correlated with disease severity...
February 27, 2018: Journal of Experimental Medicine
Jason D Ulrich, Tyler K Ulland, Thomas E Mahan, Sofie Nyström, K Peter Nilsson, Wilbur M Song, Yingyue Zhou, Mariska Reinartz, Seulah Choi, Hong Jiang, Floy R Stewart, Elise Anderson, Yaming Wang, Marco Colonna, David M Holtzman
One of the hallmarks of Alzheimer's disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-β (Aβ) peptide. Apolipoprotein E (ApoE) influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric Aβ in the brain. In addition to influencing Aβ metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APPPS1ΔE9 and APPPS1-21 transgenic mice...
February 26, 2018: Journal of Experimental Medicine
Stefanie Schmidt, Neele Schumacher, Jeanette Schwarz, Simone Tangermann, Lukas Kenner, Michaela Schlederer, Maria Sibilia, Markus Linder, Annelore Altendorf-Hofmann, Thomas Knösel, Elisabeth S Gruber, Georg Oberhuber, Julia Bolik, Ateequr Rehman, Anupam Sinha, Juliane Lokau, Philipp Arnold, Anne-Sophie Cabron, Friederike Zunke, Christoph Becker-Pauly, Adele Preaudet, Paul Nguyen, Jennifer Huynh, Shoukat Afshar-Sterle, Ashwini L Chand, Jürgen Westermann, Peter J Dempsey, Christoph Garbers, Dirk Schmidt-Arras, Philip Rosenstiel, Tracy Putoczki, Matthias Ernst, Stefan Rose-John
Colorectal cancer is treated with antibodies blocking epidermal growth factor receptor (EGF-R), but therapeutic success is limited. EGF-R is stimulated by soluble ligands, which are derived from transmembrane precursors by ADAM17-mediated proteolytic cleavage. In mouse intestinal cancer models in the absence of ADAM17, tumorigenesis was almost completely inhibited, and the few remaining tumors were of low-grade dysplasia. RNA sequencing analysis demonstrated down-regulation of STAT3 and Wnt pathway components...
February 22, 2018: Journal of Experimental Medicine
Jie Yang, Ferry Cornelissen, Natalie Papazian, Rogier M Reijmers, Miriam Llorian, Tom Cupedo, Mark Coles, Benedict Seddon
IL-7 is essential for the development and homeostasis of T and B lymphocytes and is critical for neonatal lymph node organogenesis because Il7-/- mice lack normal lymph nodes. Whether IL-7 is a continued requirement for normal lymph node structure and function is unknown. To address this, we ablated IL-7 function in normal adult hosts. Either inducible Il7 gene deletion or IL-7R blockade in adults resulted in a rapid loss of lymph node cellularity and a corresponding defect in lymphocyte entry into lymph nodes...
February 22, 2018: Journal of Experimental Medicine
Stefan Uderhardt, Jochen A Ackermann, Tobias Fillep, Victoria J Hammond, Johann Willeit, Peter Santer, Manuel Mayr, Markus Biburger, Meike Miller, Katie R Zellner, Konstantin Stark, Alexander Zarbock, Jan Rossaint, Irene Schubert, Dirk Mielenz, Barbara Dietel, Dorette Raaz-Schrauder, Cihan Ay, Thomas Gremmel, Johannes Thaler, Christian Heim, Martin Herrmann, Peter W Collins, Gernot Schabbauer, Nigel Mackman, David Voehringer, Jerry L Nadler, James J Lee, Steffen Massberg, Manfred Rauh, Stefan Kiechl, Georg Schett, Valerie B O'Donnell, Gerhard Krönke
No abstract text is available yet for this article.
February 20, 2018: Journal of Experimental Medicine
Ander Abarrategi, Syed A Mian, Diana Passaro, Kevin Rouault-Pierre, William Grey, Dominique Bonnet
Xenotransplantation of patient-derived samples in mouse models has been instrumental in depicting the role of hematopoietic stem and progenitor cells in the establishment as well as progression of hematological malignancies. The foundations for this field of research have been based on the development of immunodeficient mouse models, which provide normal and malignant human hematopoietic cells with a supportive microenvironment. Immunosuppressed and genetically modified mice expressing human growth factors were key milestones in patient-derived xenograft (PDX) models, highlighting the importance of developing humanized microenvironments...
February 16, 2018: Journal of Experimental Medicine
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