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Journal of Experimental Medicine

Musheng Bao, York Wang, Ying Liu, Peiqing Shi, Hongbo Lu, Wenwen Sha, Leiyun Weng, Shino Hanabuchi, Jun Qin, Joel Plumas, Laurence Chaperot, Zhiqiang Zhang, Yong-Jun Liu
Plasmacytoid dendritic cells (pDCs) rapidly produce large amounts of type 1 interferon (IFN) after Toll-like receptor 7 and 9 engagements. This specialized function of type 1 IFN production is directly linked to the constitutive expression of IRF7, the master transcription factor for type 1 IFN production. However, the IRF7 regulatory network in pDCs remains largely unknown. In this study, we identify that the transcription factor NFATC3 specifically binds to IRF7 and enhances IRF7-mediated IFN production. Furthermore, knockout of NFATC3 greatly reduced the CpG DNA-induced nuclear translocation of IRF7, which resulted in impaired type 1 IFN production in vitro and in vivo...
October 3, 2016: Journal of Experimental Medicine
Ana Textor, Karin Schmidt, Peter-M Kloetzel, Bianca Weißbrich, Cynthia Perez, Jehad Charo, Kathleen Anders, John Sidney, Alessandro Sette, Ton N M Schumacher, Christin Keller, Dirk H Busch, Ulrike Seifert, Thomas Blankenstein
Adoptive T cell therapy (ATT) can achieve regression of large tumors in mice and humans; however, tumors frequently recur. High target peptide-major histocompatibility complex-I (pMHC) affinity and T cell receptor (TCR)-pMHC affinity are thought to be critical to preventing relapse. Here, we show that targeting two epitopes of the same antigen in the same cancer cells via monospecific T cells, which have similar pMHC and pMHC-TCR affinity, results in eradication of large, established tumors when targeting the apparently subdominant but not the dominant epitope...
October 3, 2016: Journal of Experimental Medicine
Brooke A Napier, Sky W Brubaker, Timothy E Sweeney, Patrick Monette, Greggory H Rothmeier, Nina A Gertsvolf, Andreas Puschnik, Jan E Carette, Purvesh Khatri, Denise M Monack
Cell death and release of proinflammatory mediators contribute to mortality during sepsis. Specifically, caspase-11-dependent cell death contributes to pathology and decreases in survival time in sepsis models. Priming of the host cell, through TLR4 and interferon receptors, induces caspase-11 expression, and cytosolic LPS directly stimulates caspase-11 activation, promoting the release of proinflammatory cytokines through pyroptosis and caspase-1 activation. Using a CRISPR-Cas9-mediated genome-wide screen, we identified novel mediators of caspase-11-dependent cell death...
October 3, 2016: Journal of Experimental Medicine
Ran Afik, Ehud Zigmond, Milena Vugman, Mordehay Klepfish, Elee Shimshoni, Metsada Pasmanik-Chor, Anjana Shenoy, Elad Bassat, Zamir Halpern, Tamar Geiger, Irit Sagi, Chen Varol
Tumor-associated macrophages (TAMs) promote tumor development, invasion, and dissemination by various mechanisms. In this study, using an orthotopic colorectal cancer (CRC) model, we found that monocyte-derived TAMs advance tumor development by the remodeling of its extracellular matrix (ECM) composition and structure. Unbiased transcriptomic and proteomic analyses of (a) TAM-abundant and -deficient tumor tissues and (b) sorted tumor-associated and -resident colonic macrophage subpopulations defined a distinct TAM-induced ECM molecular signature composed of an ensemble of matricellular proteins and remodeling enzymes they provide to the tumor microenvironment...
October 3, 2016: Journal of Experimental Medicine
Elena M Cortizas, Astrid Zahn, Shiva Safavi, Joseph A Reed, Francisco Vega, Javier M Di Noia, Ramiro E Verdun
Activation-induced deaminase (AID) initiates antibody gene diversification by creating G:U mismatches in the immunoglobulin loci. However, AID also deaminates nonimmunoglobulin genes, and failure to faithfully repair these off-target lesions can cause B cell lymphoma. In this study, we identify a mechanism by which processing of G:U produced by AID at the telomeres can eliminate B cells at risk of genomic instability. We show that telomeres are off-target substrates of AID and that B cell proliferation depends on protective repair by uracil-DNA glycosylase (UNG)...
October 3, 2016: Journal of Experimental Medicine
Per Holmfeldt, Miguel Ganuza, Himangi Marathe, Bing He, Trent Hall, Guolian Kang, Joseph Moen, Jennifer Pardieck, Angelica C Saulsberry, Alba Cico, Ludovic Gaut, Daniel McGoldrick, David Finkelstein, Kai Tan, Shannon McKinney-Freeman
No abstract text is available yet for this article.
September 27, 2016: Journal of Experimental Medicine
Yue Liu, Ting-Ting Wang, Ran Zhang, Wen-Yan Fu, Xu Wang, Fang Wang, Peng Gao, Yang-Nan Ding, Yan Xie, De-Long Hao, Hou-Zao Chen, De-Pei Liu
Abdominal aortic aneurysm (AAA), characterized by a localized dilation of the abdominal aorta, is a life-threatening vascular pathology. Because of the current lack of effective treatment for AAA rupture, prevention is of prime importance for AAA management. Calorie restriction (CR) is a nonpharmacological intervention that delays the aging process and provides various health benefits. However, whether CR prevents AAA formation remains untested. In this study, we subjected Apoe(-/-) mice to 12 wk of CR and then examined the incidence of angiotensin II (AngII)-induced AAA formation...
September 26, 2016: Journal of Experimental Medicine
Luhua H Zhang, June Ho Shin, Mikel D Haggadone, John B Sunwoo
A tissue-resident population of natural killer cells (NK cells) in the liver has recently been described to have the unique capacity to confer immunological memory in the form of hapten-specific contact hypersensitivity independent of T and B cells. Factors regulating the development and maintenance of these liver-resident NK cells are poorly understood. The aryl hydrocarbon receptor (AhR) is a transcription factor modulated by exogenous and endogenous ligands that is important in the homeostasis of immune cells at barrier sites, such as the skin and gut...
September 26, 2016: Journal of Experimental Medicine
Ka Lun Cheung, Rachael Jarrett, Sumithra Subramaniam, Maryam Salimi, Danuta Gutowska-Owsiak, Yi-Ling Chen, Clare Hardman, Luzheng Xue, Vincenzo Cerundolo, Graham Ogg
Psoriasis is a chronic inflammatory skin disease associated with a T helper 17 response. Yet, it has proved challenging to identify relevant peptide-based T cell antigens. Antigen-presenting Langerhans cells show a differential migration phenotype in psoriatic lesions and express constitutively high levels of CD1a, which presents lipid antigens to T cells. In addition, phospholipase A2 (PLA2) is highly expressed in psoriatic lesions and is known to generate neolipid skin antigens for recognition by CD1a-reactive T cells...
September 26, 2016: Journal of Experimental Medicine
Rui Yang, April R Masters, Karen A Fortner, Devin P Champagne, Natalia Yanguas-Casás, Daniel J Silberger, Casey T Weaver, Laura Haynes, Mercedes Rincon
IL-6 is known to contribute to the differentiation of CD4(+) T cells into different subsets of effector T helper cells. Less is known about the potential of IL-6 in regulating CD8(+) T cell effector function. Here, we identify IL-6 as a master regulator of IL-21 in effector CD8(+) T cells. IL-6 promotes the differentiation of a subset of naive CD8(+) T cells that express IL-6R into a unique population of effector CD8(+) T cells characterized by the production of high levels of IL-21 and low levels of IFN-γ...
September 26, 2016: Journal of Experimental Medicine
Yasuhiro Kishi, Takaaki Kondo, Sheng Xiao, Nir Yosef, Jellert Gaublomme, Chuan Wu, Chao Wang, Norio Chihara, Aviv Regev, Nicole Joller, Vijay K Kuchroo
Th17 cells are key players in defense against pathogens and maintaining tissue homeostasis, but also act as critical drivers of autoimmune diseases. Based on single-cell RNA-seq profiling of pathogenic versus nonpathogenic Th17 cells, we identified protein C receptor (PROCR) as a cell surface molecule expressed in covariance with the regulatory module of Th17 cells. Although PROCR expression in T cells was controlled by the cooperative action of the Th17 lineage-specific transcription factors RORγt, IRF4, and STAT3, PROCR negatively regulated Th17 differentiation...
September 26, 2016: Journal of Experimental Medicine
Yi Wang, Cindy S Ma, Yun Ling, Aziz Bousfiha, Yildiz Camcioglu, Serge Jacquot, Kathryn Payne, Elena Crestani, Romain Roncagalli, Aziz Belkadi, Gaspard Kerner, Lazaro Lorenzo, Caroline Deswarte, Maya Chrabieh, Etienne Patin, Quentin B Vincent, Ingrid Müller-Fleckenstein, Bernhard Fleckenstein, Fatima Ailal, Lluis Quintana-Murci, Sylvie Fraitag, Marie-Alexandra Alyanakian, Marianne Leruez-Ville, Capucine Picard, Anne Puel, Jacinta Bustamante, Stéphanie Boisson-Dupuis, Marie Malissen, Bernard Malissen, Laurent Abel, Alain Hovnanian, Luigi D Notarangelo, Emmanuelle Jouanguy, Stuart G Tangye, Vivien Béziat, Jean-Laurent Casanova
Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell-intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis...
September 19, 2016: Journal of Experimental Medicine
Romain Roncagalli, Margot Cucchetti, Nicolas Jarmuzynski, Claude Grégoire, Elise Bergot, Stéphane Audebert, Emilie Baudelet, Marisa Goncalves Menoita, Anais Joachim, Stéphane Durand, Miloslav Suchanek, Frédéric Fiore, Lichen Zhang, Yinming Liang, Luc Camoin, Marie Malissen, Bernard Malissen
The RLTPR cytosolic protein, also known as CARMIL2, is essential for CD28 co-stimulation in mice, but its importance in human T cells and mode of action remain elusive. Here, using affinity purification followed by mass spectrometry analysis, we showed that RLTPR acts as a scaffold, bridging CD28 to the CARD11/CARMA1 cytosolic adaptor and to the NF-κB signaling pathway, and identified proteins not found before within the CD28 signaling pathway. We further demonstrated that RLTPR is essential for CD28 co-stimulation in human T cells and that its noncanonical pleckstrin-homology domain, leucine-rich repeat domain, and proline-rich region were mandatory for that task...
September 19, 2016: Journal of Experimental Medicine
Zhenhua Yang, Kushani Shah, Alireza Khodadadi-Jamayran, Hao Jiang
As the major histone H3K4 methyltransferases in mammals, the Set1/Mll complexes play important roles in animal development and are associated with many diseases, including hematological malignancies. However, the role of the H3K4 methylation activity of these complexes in fate determination of hematopoietic stem and progenitor cells (HSCs and HPCs) remains elusive. Here, we address this question by generating a conditional knockout mouse for Dpy30, which is a common core subunit of all Set1/Mll complexes and facilitates genome-wide H3K4 methylation in cells...
September 19, 2016: Journal of Experimental Medicine
Huaijian Guo, Stacey A Cranert, Yan Lu, Ming-Chao Zhong, Shaohua Zhang, Jun Chen, Rui Li, Sarah E Mahl, Ning Wu, Dominique Davidson, Stephen N Waggoner, André Veillette
No abstract text is available yet for this article.
September 19, 2016: Journal of Experimental Medicine
Alejo Chorny, Sandra Casas-Recasens, Jordi Sintes, Meimei Shan, Nadia Polentarutti, Ramón García-Escudero, A Cooper Walland, John R Yeiser, Linda Cassis, Jorge Carrillo, Irene Puga, Cristina Cunha, Hélder Bastos, Fernando Rodrigues, João F Lacerda, António Morais, Rebeca Dieguez-Gonzalez, Peter S Heeger, Giovanni Salvatori, Agostinho Carvalho, Adolfo Garcia-Sastre, J Magarian Blander, Alberto Mantovani, Cecilia Garlanda, Andrea Cerutti
Pentraxin 3 (PTX3) is a fluid-phase pattern recognition receptor of the humoral innate immune system with ancestral antibody-like properties but unknown antibody-inducing function. In this study, we found binding of PTX3 to splenic marginal zone (MZ) B cells, an innate-like subset of antibody-producing lymphocytes strategically positioned at the interface between the circulation and the adaptive immune system. PTX3 was released by a subset of neutrophils that surrounded the splenic MZ and expressed an immune activation-related gene signature distinct from that of circulating neutrophils...
September 19, 2016: Journal of Experimental Medicine
Takanobu Tagawa, Manuel Albanese, Mickaël Bouvet, Andreas Moosmann, Josef Mautner, Vigo Heissmeyer, Christina Zielinski, Dominik Lutter, Jonathan Hoser, Maximilian Hastreiter, Mitch Hayes, Bill Sugden, Wolfgang Hammerschmidt
Epstein-Barr virus (EBV) is a tumor virus that establishes lifelong infection in most of humanity, despite eliciting strong and stable virus-specific immune responses. EBV encodes at least 44 miRNAs, most of them with unknown function. Here, we show that multiple EBV miRNAs modulate immune recognition of recently infected primary B cells, EBV's natural target cells. EBV miRNAs collectively and specifically suppress release of proinflammatory cytokines such as IL-12, repress differentiation of naive CD4(+) T cells to Th1 cells, interfere with peptide processing and presentation on HLA class II, and thus reduce activation of cytotoxic EBV-specific CD4(+) effector T cells and killing of infected B cells...
September 19, 2016: Journal of Experimental Medicine
Alex R D Delbridge, Swee Heng Milon Pang, Cassandra J Vandenberg, Stephanie Grabow, Brandon J Aubrey, Lin Tai, Marco J Herold, Andreas Strasser
Neoplastic transformation is driven by oncogenic lesions that facilitate unrestrained cell expansion and resistance to antiproliferative signals. These oncogenic DNA lesions, acquired through errors in DNA replication, gene recombination, or extrinsically imposed damage, are thought to activate multiple tumor suppressive pathways, particularly apoptotic cell death. DNA damage induces apoptosis through well-described p53-mediated induction of PUMA and NOXA. However, loss of both these mediators (even together with defects in p53-mediated induction of cell cycle arrest and cell senescence) does not recapitulate the tumor susceptibility observed in p53(-/-) mice...
September 19, 2016: Journal of Experimental Medicine
Eng M Tan, Josef S Smolen
When studies on rheumatoid arthritis (RA) that were made many decades ago and could be considered "historical" in nature are analyzed in the context of recent observations, important insights on RA and on the function of rheumatoid factor (RF) become apparent. RF in the role of antibody to immune complexes (ICs) appears to be involved in activation of the complement system and in the production of chemotactic and inflammatory mediators, creating a condition that can be sustained and reinitiated. In the synovial cavity, a state of nonresolving inflammation is produced with the formation of citrullinated protein antigen-antibody complexes or other forms of ICs...
September 19, 2016: Journal of Experimental Medicine
Ningwen Tai, Jian Peng, Fuqiang Liu, Elke Gulden, Youjia Hu, Xiaojun Zhang, Li Chen, F Susan Wong, Li Wen
Both animal model and human studies indicate that commensal bacteria may modify type 1 diabetes (T1D) development. However, the underlying mechanisms by which gut microbes could trigger or protect from diabetes are not fully understood, especially the interaction of commensal bacteria with pathogenic CD8 T cells. In this study, using islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-reactive CD8 T cell receptor NY8.3 transgenic nonobese diabetic mice, we demonstrated that MyD88 strongly modulates CD8(+) T cell-mediated T1D development via the gut microbiota...
September 19, 2016: Journal of Experimental Medicine
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