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Journal of Experimental Medicine

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https://www.readbyqxmd.com/read/28082359/class-ii-mhc-independent-suppressive-adhesion-of-dendritic-cells-by-regulatory-t-cells-in-vivo
#1
Jiacong Yan, Bo Liu, Yan Shi, Hai Qi
Regulatory T (T reg) cells are essential for peripheral homeostasis and known to target and suppress dendritic cells (DCs). One important mechanism is through prolonged interaction between antigen-specific T reg cells and DCs that down-regulates the co-stimulatory capacity of DCs. However, the dynamics and TCR specificities of such T reg cell-DC interaction and its relevance to the suppressive outcomes for individual DCs have not been clarified. To gain insights into the underlying cellular events in vivo, we analyzed individual T reg cell-DC interaction events in lymph nodes by intravital microscopy...
January 12, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28082358/strong-adhesion-by-regulatory-t-cells-induces-dendritic-cell-cytoskeletal-polarization-and-contact-dependent-lethargy
#2
Jiahuan Chen, Anutosh Ganguly, Ashley D Mucsi, Junchen Meng, Jiacong Yan, Pascal Detampel, Fay Munro, Zongde Zhang, Mei Wu, Aswin Hari, Melanie D Stenner, Wencheng Zheng, Paul Kubes, Tie Xia, Matthias W Amrein, Hai Qi, Yan Shi
Dendritic cells are targeted by regulatory T (T reg) cells, in a manner that operates as an indirect mode of T cell suppression. In this study, using a combination of single-cell force spectroscopy and structured illumination microscopy, we analyze individual T reg cell-DC interaction events and show that T reg cells exhibit strong intrinsic adhesiveness to DCs. This increased DC adhesion reduces the ability of contacted DCs to engage other antigen-specific cells. We show that this unusually strong LFA-1-dependent adhesiveness of T reg cells is caused in part by their low calpain activities, which normally release integrin-cytoskeleton linkage, and thereby reduce adhesion...
January 12, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28082357/defective-atg16l1-mediated-removal-of-ire1%C3%AE-drives-crohn-s-disease-like-ileitis
#3
Markus Tschurtschenthaler, Timon E Adolph, Jonathan W Ashcroft, Lukas Niederreiter, Richa Bharti, Svetlana Saveljeva, Joya Bhattacharyya, Magdalena B Flak, David Q Shih, Gwenny M Fuhler, Miles Parkes, Kenji Kohno, Takao Iwawaki, C Janneke van der Woude, Heather P Harding, Andrew M Smith, Maikel P Peppelenbosch, Stephan R Targan, David Ron, Philip Rosenstiel, Richard S Blumberg, Arthur Kaser
ATG16L1(T300A), a major risk polymorphism in Crohn's disease (CD), causes impaired autophagy, but it has remained unclear how this predisposes to CD. In this study, we report that mice with Atg16l1 deletion in intestinal epithelial cells (IECs) spontaneously develop transmural ileitis phenocopying ileal CD in an age-dependent manner, driven by the endoplasmic reticulum (ER) stress sensor IRE1α. IRE1α accumulates in Paneth cells of Atg16l1(ΔIEC) mice, and humans homozygous for ATG16L1(T300A) exhibit a corresponding increase of IRE1α in intestinal epithelial crypts...
January 12, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28082356/ikk%C3%AE-controls-atg16l1-degradation-to-prevent-er-stress-during-inflammation
#4
Michaela A Diamanti, Jalaj Gupta, Moritz Bennecke, Tiago De Oliveira, Mallika Ramakrishnan, Anne K Braczynski, Benjamin Richter, Petra Beli, Yinling Hu, Maya Saleh, Michel Mittelbronn, Ivan Dikic, Florian R Greten
Inhibition of the IκB kinase complex (IKK) has been implicated in the therapy of several chronic inflammatory diseases including inflammatory bowel diseases. In this study, using mice with an inactivatable IKKα kinase (Ikkα(AA/AA)), we show that loss of IKKα function markedly impairs epithelial regeneration in a model of acute colitis. Mechanistically, this is caused by compromised secretion of cytoprotective IL-18 from IKKα-mutant intestinal epithelial cells because of elevated caspase 12 activation during an enhanced unfolded protein response (UPR)...
January 12, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28069639/correction-noncanonical-wnt-5a-signaling-impairs-endogenous-lung-repair-in-copd
#5
Hoeke A Baarsma, Wioletta Skronska-Wasek, Kathrin Mutze, Florian Ciolek, Darcy E Wagner, Gerrit John-Schuster, Katharina Heinzelmann, Andreas Günther, Ken R Bracke, Maylis Dagouassat, Jorge Boczkowski, Guy G Brusselle, Ron Smits, Oliver Eickelberg, Ali Ö Yildirim, Melanie Königshoff
No abstract text is available yet for this article.
January 9, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28057805/cns-targeted-autoimmunity-leads-to-increased-influenza-mortality-in-mice
#6
Justin D Glenn, Matthew D Smith, Pei Xue, Yee Chan-Li, Samuel Collins, Peter A Calabresi, Maureen R Horton, Katharine A Whartenby
The discovery that central nervous system (CNS)-targeted autoreactive T cells required a process of licensing in the lung revealed an unexpected relationship between these organs. The clinical and immunological significance of this finding is bidirectional in that it showed not only a mechanism by which T cells become pathogenic before entering the CNS, but also the potential for this process to influence lung immunity as well. Epidemiological studies have shown that people with multiple sclerosis (MS) suffer from increased morbidity and mortality from infectious diseases, independent of immunosuppressive therapies...
January 5, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28057804/cell-cycle-progression-dictates-the-requirement-for-bcl2-in-natural-killer-cell-survival
#7
Charlotte Viant, Sophie Guia, Robert J Hennessy, Jai Rautela, Kim Pham, Claire Bernat, Wilford Goh, Yuhao Jiao, Rebecca Delconte, Michael Roger, Vanina Simon, Fernando Souza-Fonseca-Guimaraes, Stephanie Grabow, Gabrielle T Belz, Benjamin T Kile, Andreas Strasser, Daniel Gray, Phillip D Hodgkin, Bruce Beutler, Eric Vivier, Sophie Ugolini, Nicholas D Huntington
Natural killer (NK) cells are innate lymphoid cells with antitumor functions. Using an N-ethyl-N-nitrosourea (ENU)-induced mutagenesis screen in mice, we identified a strain with an NK cell deficiency caused by a hypomorphic mutation in the Bcl2 (B cell lymphoma 2) gene. Analysis of these mice and the conditional deletion of Bcl2 in NK cells revealed a nonredundant intrinsic requirement for BCL2 in NK cell survival. In these mice, NK cells in cycle were protected against apoptosis, and NK cell counts were restored in inflammatory conditions, suggesting a redundant role for BCL2 in proliferating NK cells...
January 5, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28049627/dissection-of-sap-dependent-and-sap-independent-slam-family-signaling-in-nkt-cell-development-and-humoral-immunity
#8
Shasha Chen, Chenxu Cai, Zehua Li, Guangao Liu, Yuande Wang, Marzenna Blonska, Dan Li, Juan Du, Xin Lin, Meixiang Yang, Zhongjun Dong
Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) mutations in X-linked lymphoproliferative disease (XLP) lead to defective NKT cell development and impaired humoral immunity. Because of the redundancy of SLAM family receptors (SFRs) and the complexity of SAP actions, how SFRs and SAP mediate these processes remains elusive. Here, we examined NKT cell development and humoral immunity in mice completely deficient in SFR. We found that SFR deficiency severely impaired NKT cell development...
January 3, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28031480/cd70-cd27-signaling-promotes-blast-stemness-and-is-a-viable-therapeutic-target-in-acute-myeloid-leukemia
#9
Carsten Riether, Christian M Schürch, Elias D Bührer, Magdalena Hinterbrandner, Anne-Laure Huguenin, Sabine Hoepner, Inti Zlobec, Thomas Pabst, Ramin Radpour, Adrian F Ochsenbein
Aberrant proliferation, symmetric self-renewal, increased survival, and defective differentiation of malignant blasts are key oncogenic drivers in acute myeloid leukemia (AML). Stem cell gene signatures predict poor prognosis in AML patients; however, with few exceptions, these deregulated molecular pathways cannot be targeted therapeutically. In this study, we demonstrate that the TNF superfamily ligand-receptor pair CD70/CD27 is expressed on AML blasts and AML stem/progenitor cells. CD70/CD27 signaling in AML cells activates stem cell gene expression programs, including the Wnt pathway, and promotes symmetric cell divisions and proliferation...
December 28, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28031479/peptidylarginine-deiminase-4-promotes-age-related-organ-fibrosis
#10
Kimberly Martinod, Thilo Witsch, Luise Erpenbeck, Alexander Savchenko, Hideki Hayashi, Deya Cherpokova, Maureen Gallant, Maximilian Mauler, Stephen M Cifuni, Denisa D Wagner
Aging promotes inflammation, a process contributing to fibrosis and decline in organ function. The release of neutrophil extracellular traps (NETs [NETosis]), orchestrated by peptidylarginine deiminase 4 (PAD4), damages organs in acute inflammatory models. We determined that NETosis is more prevalent in aged mice and investigated the role of PAD4/NETs in age-related organ fibrosis. Reduction in fibrosis was seen in the hearts and lungs of aged PAD4(-/-) mice compared with wild-type (WT) mice. An increase in left ventricular interstitial collagen deposition and a decline in systolic and diastolic function were present only in WT mice, and not in PAD4(-/-) mice...
December 28, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28031478/trim65-catalized-ubiquitination-is-essential-for-mda5-mediated-antiviral-innate-immunity
#11
Xueting Lang, Tiantian Tang, Tengchuan Jin, Chen Ding, Rongbin Zhou, Wei Jiang
MDA5 plays a critical role in antiviral innate immunity by functioning as a cytoplasmic double-stranded RNA sensor that can activate type I interferon signaling pathways, but the mechanism for the activation of MDA5 is poorly understood. Here, we show that TRIM65 specifically interacts with MDA5 and promotes K63-linked ubiquitination of MDA5 at lysine 743, which is critical for MDA5 oligomerization and activation. Trim65 deficiency abolishes MDA5 agonist or encephalomyocarditis virus (EMCV)-induced interferon regulatory factor 3 (IRF3) activation and type I interferon production but has no effect on retinoic acid-inducible I (RIG-I), Toll-like receptor 3 (TLR3), or cyclic GMP-AMP synthase signaling pathways...
December 28, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28031477/lipin-2-regulates-nlrp3-inflammasome-by-affecting-p2x7-receptor-activation
#12
Gema Lordén, Itziar Sanjuán-García, Nagore de Pablo, Clara Meana, Inés Alvarez-Miguel, M Teresa Pérez-García, Pablo Pelegrín, Jesús Balsinde, María A Balboa
Mutations in human LPIN2 produce a disease known as Majeed syndrome, the clinical manifestations of which are ameliorated by strategies that block IL-1β or its receptor. However the role of lipin-2 during IL-1β production remains elusive. We show here that lipin-2 controls excessive IL-1β formation in primary human and mouse macrophages by several mechanisms, including activation of the inflammasome NLRP3. Lipin-2 regulates MAPK activation, which mediates synthesis of pro-IL-1β during inflammasome priming...
December 28, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28031476/5-hydroxytryptamine-synthesized-in-the-aorta-gonad-mesonephros-regulates-hematopoietic-stem-and-progenitor-cell-survival
#13
Junhua Lv, Lu Wang, Ya Gao, Yu-Qiang Ding, Feng Liu
The in vitro or ex vivo production of transplantable hematopoietic stem cells (HSCs) holds great promise for the treatment of hematological diseases in the clinic. However, HSCs have not been produced from either embryonic or induced pluripotent stem cells. In this study, we report that 5-hydroxytryptamine (5-HT; also called serotonin) can enhance the generation of hematopoietic stem and progenitor cells (HSPCs) in vitro and is essential for the survival of HSPCs in vivo during embryogenesis. In tryptophan hydroxylase 2-deficient embryos, a decrease in 5-HT synthesized in the aorta-gonad-mesonephros leads to apoptosis of nascent HSPCs...
December 28, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28028152/pharmacologic-inhibition-of-hsp90-to-prevent-glt-1-degradation-as-an-effective-therapy-for-epilepsy
#14
Longze Sha, Xueqin Wang, Jing Li, Xinze Shi, Liwen Wu, Yan Shen, Qi Xu
The glutamate transporter GLT-1 is critical for the maintenance of low interstitial glutamate concentrations. Loss of GLT-1 is commonly observed in neurological disorders, including temporal lobe epilepsy (TLE). Despite the hypothesis that targeting the mechanisms of GLT-1 deficiency may be a novel strategy for treating drug-resistant epilepsy, the underlying molecular cascade remains largely unknown. Here, we show that Hsp90β is up-regulated in reactive astrocytes of the epileptic hippocampus in patients with TLE and mouse models of epilepsy...
December 27, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27994070/characterization-of-meningeal-type-2-innate-lymphocytes-and-their-response-to-cns-injury
#15
Sachin P Gadani, Igor Smirnov, Ashtyn T Smith, Christopher C Overall, Jonathan Kipnis
The meningeal space is occupied by a diverse repertoire of immune cells. Central nervous system (CNS) injury elicits a rapid immune response that affects neuronal survival and recovery, but the role of meningeal inflammation remains poorly understood. Here, we describe type 2 innate lymphocytes (ILC2s) as a novel cell type resident in the healthy meninges that are activated after CNS injury. ILC2s are present throughout the naive mouse meninges, though are concentrated around the dural sinuses, and have a unique transcriptional profile...
December 19, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28043986/a-time-of-change
#16
EDITORIAL
Carl F Nathan, Michel C Nussenzweig, Teodoro Pulvirenti
As Co-Chairs and Executive Editor of The Journal of Experimental Medicine, we write to share some changes that will help us provide JEM authors with the best service we can.
January 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28028151/lrch1-interferes-with-dock8-cdc42-induced-t-cell-migration-and-ameliorates-experimental-autoimmune-encephalomyelitis
#17
Xiaoyan Xu, Lei Han, Guixian Zhao, Shengjie Xue, Yunzhen Gao, Jun Xiao, Shicheng Zhang, Peng Chen, Zhi-Ying Wu, Jianping Ding, Ronggui Hu, Bin Wei, Hongyan Wang
Directional autoreactive CD4(+) T cell migration into the central nervous system plays a critical role in multiple sclerosis. Recently, DOCK8 was identified as a guanine-nucleotide exchange factor (GEF) for Cdc42 activation and has been associated with human mental retardation. Little is known about whether DOCK8 is related to multiple sclerosis (MS) and how to restrict its GEF activity. Using two screening systems, we found that LRCH1 competes with Cdc42 for interaction with DOCK8 and restrains T cell migration...
January 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28011866/the-aryl-hydrocarbon-receptor-controls-cell-fate-decisions-in-b-cells
#18
Bharat Vaidyanathan, Ashutosh Chaudhry, William T Yewdell, Davide Angeletti, Wei-Feng Yen, Adam K Wheatley, Christopher A Bradfield, Adrian B McDermott, Jonathan W Yewdell, Alexander Y Rudensky, Jayanta Chaudhuri
Generation of cellular heterogeneity is an essential feature of the adaptive immune system. This is best exemplified during humoral immune response when an expanding B cell clone assumes multiple cell fates, including class-switched B cells, antibody-secreting plasma cells, and memory B cells. Although each cell type is essential for immunity, their generation must be exquisitely controlled because a class-switched B cell cannot revert back to the parent isotype, and a terminally differentiated plasma cell cannot contribute to the memory pool...
January 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28011865/leukotrienes-provide-an-nfat-dependent-signal-that-synergizes-with-il-33-to-activate-ilc2s
#19
Jakob von Moltke, Claire E O'Leary, Nora A Barrett, Yoshihide Kanaoka, K Frank Austen, Richard M Locksley
Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2 cells) are the primary source of interleukin 5 (IL-5) and IL-13 during type 2 (allergic) inflammation in the lung. In Th2 cells, T cell receptor (TCR) signaling activates the transcription factors nuclear factor of activated T cells (NFAT), nuclear factor κB (NF-κB), and activator protein 1 (AP-1) to induce type 2 cytokines. ILC2s lack a TCR and respond instead to locally produced cytokines such as IL-33. Although IL-33 induces AP-1 and NF-κB, NFAT signaling has not been described in ILC2s...
January 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28011864/combined-immunodeficiency-and-epstein-barr-virus-induced-b-cell-malignancy-in-humans-with-inherited-cd70-deficiency
#20
Hassan Abolhassani, Emily S J Edwards, Aydan Ikinciogullari, Huie Jing, Stephan Borte, Marcus Buggert, Likun Du, Mami Matsuda-Lennikov, Rosa Romano, Rozina Caridha, Sangeeta Bade, Yu Zhang, Juliet Frederiksen, Mingyan Fang, Sevgi Kostel Bal, Sule Haskologlu, Figen Dogu, Nurdan Tacyildiz, Helen F Matthews, Joshua J McElwee, Emma Gostick, David A Price, Umaimainthan Palendira, Asghar Aghamohammadi, Bertrand Boisson, Nima Rezaei, Annika C Karlsson, Michael J Lenardo, Jean-Laurent Casanova, Lennart Hammarström, Stuart G Tangye, Helen C Su, Qiang Pan-Hammarström
In this study, we describe four patients from two unrelated families of different ethnicities with a primary immunodeficiency, predominantly manifesting as susceptibility to Epstein-Barr virus (EBV)-related diseases. Three patients presented with EBV-associated Hodgkin's lymphoma and hypogammaglobulinemia; one also had severe varicella infection. The fourth had viral encephalitis during infancy. Homozygous frameshift or in-frame deletions in CD70 in these patients abolished either CD70 surface expression or binding to its cognate receptor CD27...
January 2017: Journal of Experimental Medicine
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