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Journal of Experimental Medicine

Difeng Fang, Kairong Cui, Kairui Mao, Gangqing Hu, Rao Li, Mingzhu Zheng, Nicolas Riteau, Steven L Reiner, Alan Sher, Keji Zhao, Jinfang Zhu
T follicular helper (Tfh) cells express transcription factor BCL-6 and cytokine IL-21. Mature Tfh cells are also capable of producing IFN-γ without expressing the Th1 transcription factor T-bet. Whether this IFN-γ-producing Tfh population represents a unique Tfh subset with a distinct differentiation pathway is poorly understood. By using T-bet fate-mapping mouse strains, we discovered that almost all the IFN-γ-producing Tfh cells have previously expressed T-bet and express high levels of NKG2D. DNase I hypersensitivity analysis indicated that the Ifng gene locus is partially accessible in this "ex-T-bet" population with a history of T-bet expression...
September 19, 2018: Journal of Experimental Medicine
M Luisa Iruela-Arispe
In this issue of JEM , Singhal et al. ( explore the cellular mechanisms involved in endothelial cell regeneration in the liver. Using a combination of myeloablative and nonmyeloablative approaches, the authors found that repair of the endothelium is mediated by endothelial cells themselves, but when injured, endothelial cells enlist myeloid counterparts that aid in vascular repair.
September 18, 2018: Journal of Experimental Medicine
Dhaval Dixit, Susan R Schwab
In this issue of JEM , Fistonich et al. ( address how the bone marrow microenvironment supports diverse lineages through multiple developmental stages. Differential motility between pro- and preB cells results in differential IL-7 exposure, and, intriguingly, stromal cells respond to abnormal B cells by reducing Il7 .
September 18, 2018: Journal of Experimental Medicine
Siyuan Chen, Fenglin Yun, Yikun Yao, Mengtao Cao, Yifan Zhang, Jingjing Wang, Xinyang Song, Youcun Qian
Th2 immune response is critical for allergic asthma pathogenesis. Molecular mechanisms for regulating Th2 immunity are still not well understood. Here we report that the ubiquitin-specific protease USP38 is crucial for Th2-mediated allergic asthma. TCR stimulation up-regulated the USP38 level, and USP38 in turn mediated the protein stabilization of JunB, a transcription factor specific for Th2 development. Consequently, USP38 was specifically required for TCR-induced production of Th2 cytokines and Th2 development both in vitro and in vivo, and USP38-deficient mice were resistant to asthma pathogenesis induced by OVA or HDM...
September 17, 2018: Journal of Experimental Medicine
Samra Turajlic, Charles Swanton, Chris Boshoff
Chris Boshoff, Senior Vice President of Immuno-Oncology, Translational and Early Development at Pfizer, and colleagues Samra Turajlic and Charles Swanton from the Francis Crick Institute and University College London give us their personal point of view on new insights and future therapeutic approaches for renal cancer.
September 14, 2018: Journal of Experimental Medicine
Joseph Mandelbaum, Ilya A Shestopalov, Rachel E Henderson, Nicole G Chau, Birgit Knoechel, Michael J Wick, Leonard I Zon
Pluripotent cells have been used to probe developmental pathways that are involved in genetic diseases and oncogenic events. To find new therapies that would target MYB -driven tumors, we developed a pluripotent zebrafish blastomere culture system. We performed a chemical genetic screen and identified retinoic acid agonists as suppressors of c-myb expression. Retinoic acid treatment also decreased c-myb gene expression in human leukemia cells. Translocations that drive overexpression of the oncogenic transcription factor MYB are molecular hallmarks of adenoid cystic carcinoma (ACC), a malignant salivary gland tumor with no effective therapy...
September 12, 2018: Journal of Experimental Medicine
Pierre-Louis Loyher, Pauline Hamon, Marie Laviron, Aïda Meghraoui-Kheddar, Elena Goncalves, Zihou Deng, Sara Torstensson, Nadège Bercovici, Camille Baudesson de Chanville, Béhazine Combadière, Frederic Geissmann, Ariel Savina, Christophe Combadière, Alexandre Boissonnas
Tissue-resident macrophages can self-maintain without contribution of adult hematopoiesis. Herein we show that tissue-resident interstitial macrophages (Res-TAMs) in mouse lungs contribute to the pool of tumor-associated macrophages (TAMs) together with CCR2-dependent recruited macrophages (MoD-TAMs). Res-TAMs largely correlated with tumor cell growth in vivo, while MoD-TAMs accumulation was associated with enhanced tumor spreading. Both cell subsets were depleted after chemotherapy, but MoD-TAMs rapidly recovered and performed phagocytosis-mediated tumor clearance...
September 10, 2018: Journal of Experimental Medicine
Michelle N Wray-Dutra, Fahd Al Qureshah, Genita Metzler, Mohamed Oukka, Richard G James, David J Rawlings
Activated PI3K-delta syndrome (APDS) is an immunodeficiency caused by gain-of-function mutations in PIK3CD. This disease exhibits complex immune phenotypes including increased IgM, recurrent infection, and impaired vaccine responses. To better understand the impact of B cells in this disease, we generated an inducible model of the common APDS mutation (h PIK3CD -E1021K; referred to as aPIK3CD) and intercrossed these mice with B cell-specific Cre models. Mb1-aPIK3CD mice exhibited bone marrow B lymphopenia and, conversely, expansion of the peripheral innate B1a and MZ B cell compartments...
September 7, 2018: Journal of Experimental Medicine
Julián Albarrán-Juárez, Andras Iring, ShengPeng Wang, Sayali Joseph, Myriam Grimm, Boris Strilic, Nina Wettschureck, Till F Althoff, Stefan Offermanns
The vascular endothelium is constantly exposed to mechanical forces, including fluid shear stress exerted by the flowing blood. Endothelial cells can sense different flow patterns and convert the mechanical signal of laminar flow into atheroprotective signals, including eNOS activation, whereas disturbed flow in atheroprone areas induces inflammatory signaling, including NF-κB activation. How endothelial cells distinguish different flow patterns is poorly understood. Here we show that both laminar and disturbed flow activate the same initial pathway involving the mechanosensitive cation channel Piezo1, the purinergic P2Y2 receptor, and Gq /G11 -mediated signaling...
September 7, 2018: Journal of Experimental Medicine
Mahak Singhal, Xiaoting Liu, Donato Inverso, Kai Jiang, Jianing Dai, Hao He, Susanne Bartels, Weiping Li, Ashik Ahmed Abdul Pari, Nicolas Gengenbacher, Eva Besemfelder, Lijian Hui, Hellmut G Augustin, Junhao Hu
Neoangiogenesis plays a key role in diverse pathophysiological conditions, including liver regeneration. Yet, the source of new endothelial cells (ECs) remains elusive. By analyzing the regeneration of the liver vasculature in irradiation-based myeloablative and nonmyeloablative bone marrow transplantation mouse models, we discovered that neoangiogenesis in livers with intact endothelium was solely mediated by proliferation of resident ECs. However, following irradiation-induced EC damage, bone marrow-derived mononuclear cells were recruited and incorporated into the vasculature...
September 7, 2018: Journal of Experimental Medicine
Kumar Vaibhav, Molly Braun, Mohammad Badruzzaman Khan, Sumbul Fatima, Nancy Saad, Adarsh Shankar, Zenab T Khan, Ruth B S Harris, Qiuhua Yang, Yuqing Huo, Ali S Arbab, Shailendra Giri, Cargill H Alleyne, John R Vender, David C Hess, Babak Baban, Md Nasrul Hoda, Krishnan M Dhandapani
Spontaneous intracerebral hemorrhage (ICH) produces the highest acute mortality and worst outcomes of all stroke subtypes. Hematoma volume is an independent determinant of ICH patient outcomes, making clot resolution a primary goal of clinical management. Herein, remote-limb ischemic post-conditioning (RIC), the repetitive inflation-deflation of a blood pressure cuff on a limb, accelerated hematoma resolution and improved neurological outcomes after ICH in mice. Parabiosis studies revealed RIC accelerated clot resolution via a humoral-mediated mechanism...
September 6, 2018: Journal of Experimental Medicine
Shigeru Tanaka, Akira Suto, Taro Iwamoto, Takahiro Kageyama, Tomohiro Tamachi, Hiroaki Takatori, Kotaro Suzuki, Koichi Hirose, Osamu Ohara, Véronique Lefebvre, Hiroshi Nakajima
Peripherally induced regulatory T (pT reg) cells play indispensable roles in regulating gut inflammation; however, the mechanism underling the differentiation of pT reg cells under inflammatory conditions remains largely unknown. Here, we show that the expression of Sox12, a member of SoxC family, is significantly induced in T reg cells in colitic mice. We also show that TCR-NFAT signaling induces Sox12 expression in CD4+ T cells. Although Sox12 is not required for the development of thymus-derived T reg (tT reg) cells, Sox12 is involved in the development of pT reg cells under inflammatory conditions in an adoptive transfer colitis model...
September 6, 2018: Journal of Experimental Medicine
Yoshinaga Ito, Orr Ashenberg, Jason Pyrdol, Adrienne M Luoma, Orit Rozenblatt-Rosen, Matan Hofree, Elena Christian, Lucas Ferrari de Andrade, Rong En Tay, Luc Teyton, Aviv Regev, Stephanie K Dougan, Kai W Wucherpfennig
A number of autoimmunity-associated MHC class II proteins interact only weakly with the invariant chain-derived class II-associated invariant chain peptide (CLIP). CLIP dissociates rapidly from I-Ag7 even in the absence of DM, and this property is related to the type 1 diabetes-associated β57 polymorphism. We generated knock-in non-obese diabetic (NOD) mice with a single amino acid change in the CLIP segment of the invariant chain in order to moderately slow CLIP dissociation from I-Ag7 These knock-in mice had a significantly reduced incidence of spontaneous type 1 diabetes and diminished islet infiltration by CD4 T cells, in particular T cells specific for fusion peptides generated by covalent linkage of proteolytic fragments within β cell secretory granules...
September 5, 2018: Journal of Experimental Medicine
Jacquelyn Nestor, Yoshiyuki Arinuma, Tomás S Huerta, Czeslawa Kowal, Elham Nasiri, Nina Kello, Yuichiro Fujieda, Alison Bialas, Tim Hammond, Uma Sriram, Beth Stevens, Patricio T Huerta, Bruce T Volpe, Betty Diamond
Cognitive impairment occurs in 40-90% of patients with systemic lupus erythematosus (SLE), which is characterized by autoantibodies to nuclear antigens, especially DNA. We discovered that a subset of anti-DNA antibodies, termed DNRAbs, cross reacts with the N-methyl-d-aspartate receptor (NMDAR) and enhances NMDAR signaling. In patients, DNRAb presence associates with spatial memory impairment. In a mouse model, DNRAb-mediated brain pathology proceeds through an acute phase of excitotoxic neuron loss, followed by persistent alteration in neuronal integrity and spatial memory impairment...
September 5, 2018: Journal of Experimental Medicine
Johanne T Jacobsen, Luka Mesin, Styliani Markoulaki, Ariën Schiepers, Cecília B Cavazzoni, Djenet Bousbaine, Rudolf Jaenisch, Gabriel D Victora
We developed a method for rapid generation of B cell receptor (BCR) monoclonal mice expressing prerearranged Igh and Igk chains monoallelically from the Igh locus by CRISPR-Cas9 injection into fertilized oocytes. B cells from these mice undergo somatic hypermutation (SHM), class switch recombination (CSR), and affinity-based selection in germinal centers. This method combines the practicality of BCR transgenes with the ability to study Ig SHM, CSR, and affinity maturation.
September 4, 2018: Journal of Experimental Medicine
Chris Fistonich, Sandra Zehentmeier, Jeffrey J Bednarski, Runfeng Miao, Hilde Schjerven, Barry P Sleckman, João P Pereira
B cell progenitors require paracrine signals such as interleukin-7 (IL-7) provided by bone marrow stromal cells for proliferation and survival. Yet, how B cells regulate access to these signals in vivo remains unclear. Here we show that proB and IL-7+ cells form a cell circuit wired by IL-7R signaling, which controls CXCR4 and focal adhesion kinase (FAK) expression and restricts proB cell movement due to increased adhesion to IL-7+ CXCL12Hi cells. PreBCR signaling breaks this circuit by switching the preB cell behavior into a fast-moving and lower-adhesion state via increased CXCR4 and reduced FAK/α4β1 expression...
August 29, 2018: Journal of Experimental Medicine
Jolanda Brummelman, Emilia M C Mazza, Giorgia Alvisi, Federico S Colombo, Andrea Grilli, Joanna Mikulak, Domenico Mavilio, Marco Alloisio, Francesco Ferrari, Egesta Lopci, Pierluigi Novellis, Giulia Veronesi, Enrico Lugli
CD8+ T cells infiltrating tumors are largely dysfunctional, but whether a subset maintains superior functionality remains ill defined. By high-dimensional single cell analysis of millions of CD8+ T cells from 53 individuals with lung cancer, we defined those subsets that are enriched in tumors compared with cancer-free tissues and blood. Besides exhausted and activated cells, we identified CXCR5+ TIM-3- CD8+ T cells with a partial exhausted phenotype, while retaining gene networks responsible for stem-like plasticity and cytotoxicity, as revealed by single cell sequencing of the whole transcriptome...
August 28, 2018: Journal of Experimental Medicine
Nicholas Hernandez, Isabelle Melki, Huie Jing, Tanwir Habib, Susie S Y Huang, Jeffrey Danielson, Tomasz Kula, Scott Drutman, Serkan Belkaya, Vimel Rattina, Lazaro Lorenzo-Diaz, Anais Boulai, Yoann Rose, Naoki Kitabayashi, Mathieu P Rodero, Cecile Dumaine, Stéphane Blanche, Marie-Noëlle Lebras, Man Chun Leung, Lisa Sara Mathew, Bertrand Boisson, Shen-Ying Zhang, Stephanie Boisson-Dupuis, Silvia Giliani, Damien Chaussabel, Luigi D Notarangelo, Stephen J Elledge, Michael J Ciancanelli, Laurent Abel, Qian Zhang, Nico Marr, Yanick J Crow, Helen C Su, Jean-Laurent Casanova
Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient's cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable...
August 24, 2018: Journal of Experimental Medicine
Kun Yang, Ryan Huang, Haruhiko Fujihira, Tadashi Suzuki, Nan Yan
Mutations in the NGLY1 (N-glycanase 1) gene, encoding an evolutionarily conserved deglycosylation enzyme, are associated with a rare congenital disorder leading to global developmental delay and neurological abnormalities. The molecular mechanism of the NGLY1 disease and its function in tissue and immune homeostasis remain unknown. Here, we find that NGLY1 -deficient human and mouse cells chronically activate cytosolic nucleic acid-sensing pathways, leading to elevated interferon gene signature. We also find that cellular clearance of damaged mitochondria by mitophagy is impaired in the absence of NGLY1, resulting in severely fragmented mitochondria and activation of cGAS-STING as well as MDA5-MAVS pathways...
August 22, 2018: Journal of Experimental Medicine
Paramita Chakrabarty, Andrew Li, Thomas B Ladd, Michael R Strickland, Emily J Koller, Jeremy D Burgess, Cory C Funk, Pedro E Cruz, Mariet Allen, Mariya Yaroshenko, Xue Wang, Curtis Younkin, Joseph Reddy, Benjamin Lohrer, Leonie Mehrke, Brenda D Moore, Xuefei Liu, Carolina Ceballos-Diaz, Awilda M Rosario, Christopher Medway, Christopher Janus, Hong-Dong Li, Dennis W Dickson, Benoit I Giasson, Nathan D Price, Steven G Younkin, Nilüfer Ertekin-Taner, Todd E Golde
There is considerable interest in harnessing innate immunity to treat Alzheimer's disease (AD). Here, we explore whether a decoy receptor strategy using the ectodomain of select TLRs has therapeutic potential in AD. AAV-mediated expression of human TLR5 ectodomain (sTLR5) alone or fused to human IgG4 Fc (sTLR5Fc) results in robust attenuation of amyloid β (Aβ) accumulation in a mouse model of Alzheimer-type Aβ pathology. sTLR5Fc binds to oligomeric and fibrillar Aβ with high affinity, forms complexes with Aβ, and blocks Aβ toxicity...
September 3, 2018: Journal of Experimental Medicine
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