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Journal of Experimental Medicine

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https://www.readbyqxmd.com/read/28637884/vaccination-establishes-clonal-relatives-of-germinal-center-t-cells-in-the-blood-of-humans
#1
Antje Heit, Frank Schmitz, Sarah Gerdts, Britta Flach, Miranda S Moore, Jonathan A Perkins, Harlan S Robins, Alan Aderem, Paul Spearman, Georgia D Tomaras, Stephen C De Rosa, M Juliana McElrath
Germinal center T follicular helper cells (GCTfh) in lymphatic tissue are critical for B cell differentiation and protective antibody induction, but whether GCTfh establish clonal derivatives as circulating memory T cells is less understood. Here, we used markers expressed on GCTfh, CXCR5, PD1, and ICOS, to identify potential circulating CXCR5(+)CD4(+) Tfh-like cells (cTfh) in humans, and investigated their functional phenotypes, diversity, and ontogeny in paired donor blood and tonsils, and in blood after vaccination...
June 21, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28637883/niche-mediated-depletion-of-the-normal-hematopoietic-stem-cell-reservoir-by-flt3-itd-induced-myeloproliferation
#2
Adam J Mead, Wen Hao Neo, Nikolaos Barkas, Sahoko Matsuoka, Alice Giustacchini, Raffaella Facchini, Supat Thongjuea, Lauren Jamieson, Christopher A G Booth, Nicholas Fordham, Cristina Di Genua, Deborah Atkinson, Onima Chowdhury, Emmanouela Repapi, Nicki Gray, Shabnam Kharazi, Sally-Ann Clark, Tiphaine Bouriez, Petter Woll, Toshio Suda, Claus Nerlov, Sten Eirik W Jacobsen
Although previous studies suggested that the expression of FMS-like tyrosine kinase 3 (Flt3) initiates downstream of mouse hematopoietic stem cells (HSCs), FLT3 internal tandem duplications (FLT3 ITDs) have recently been suggested to intrinsically suppress HSCs. Herein, single-cell interrogation found Flt3 mRNA expression to be absent in the large majority of phenotypic HSCs, with a strong negative correlation between Flt3 and HSC-associated gene expression. Flt3-ITD knock-in mice showed reduced numbers of phenotypic HSCs, with an even more severe loss of long-term repopulating HSCs, likely reflecting the presence of non-HSCs within the phenotypic HSC compartment...
June 21, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28637882/flt3-dancing-on-the-stem-cell
#3
Mark Levis
Whether or not FLT3 mutations are present and expressed within a leukemic hematopoietic stem cell has engendered some controversy. New evidence has now been presented on this issue that could change the way we manage the disease in the future.
June 21, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28634194/zbp1-dai-ubiquitination-and-sensing-of-influenza-vrnps-activate-programmed-cell-death
#4
Sannula Kesavardhana, Teneema Kuriakose, Clifford S Guy, Parimal Samir, R K Subbarao Malireddi, Ashutosh Mishra, Thirumala-Devi Kanneganti
Innate sensing of influenza virus infection induces activation of programmed cell death pathways. We have recently identified Z-DNA-binding protein 1 (ZBP1) as an innate sensor of influenza A virus (IAV). ZBP1-mediated IAV sensing is critical for triggering programmed cell death in the infected lungs. Surprisingly, little is known about the mechanisms regulating ZBP1 activation to induce programmed cell death. Here, we report that the sensing of IAV RNA by retinoic acid inducible gene I (RIG-I) initiates ZBP1-mediated cell death via the RIG-I-MAVS-IFN-β signaling axis...
June 20, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28630089/dynamic-balance-between-master-transcription-factors-determines-the-fates-and-functions-of-cd4-t-cell-and-innate-lymphoid-cell-subsets
#5
REVIEW
Difeng Fang, Jinfang Zhu
CD4 T cells, including T regulatory cells (Treg cells) and effector T helper cells (Th cells), and recently identified innate lymphoid cells (ILCs) play important roles in host defense and inflammation. Both CD4 T cells and ILCs can be classified into distinct lineages based on their functions and the expression of lineage-specific genes, including those encoding effector cytokines, cell surface markers, and key transcription factors. It was first recognized that each lineage expresses a specific master transcription factor and the expression of these factors is mutually exclusive because of cross-regulation among these factors...
June 19, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28630088/the-islet-resident-macrophage-is-in-an-inflammatory-state-and-senses-microbial-products-in-blood
#6
Stephen T Ferris, Pavel N Zakharov, Xiaoxiao Wan, Boris Calderon, Maxim N Artyomov, Emil R Unanue, Javier A Carrero
We examined the transcriptional profiles of macrophages that reside in the islets of Langerhans of 3-wk-old non-obese diabetic (NOD), NOD.Rag1(-/-), and B6.g7 mice. Islet macrophages expressed an activation signature with high expression of Tnf, Il1b, and MHC-II at both the transcript and protein levels. These features are common with barrier macrophages of the lung and gastrointestinal tract. Moreover, injection of lipopolysaccharide induced rapid inflammatory gene expression, indicating that blood stimulants are accessible to the macrophages and that these macrophages can sense them...
June 19, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28626071/nlrx1-dampens-oxidative-stress-and-apoptosis-in-tissue-injury-via-control-of-mitochondrial-activity
#7
Geurt Stokman, Lotte Kors, Pieter J Bakker, Elena Rampanelli, Nike Claessen, Gwendoline J D Teske, Loes Butter, Harmen van Andel, Marius A van den Bergh Weerman, Per W B Larsen, Mark C Dessing, Coert J Zuurbier, Stephen E Girardin, Sandrine Florquin, Jaklien C Leemans
Mitochondrial dysfunction is the most prominent source of oxidative stress in acute and chronic kidney disease. NLRX1 is a receptor of the innate immune system that is ubiquitously expressed and localized in mitochondria. We investigated whether NLRX1 may act at the interface of metabolism and innate immunity in a model of oxidative stress. Using a chimeric mouse model for renal ischemia-reperfusion injury, we found that NLRX1 protects against mortality, mitochondrial damage, and epithelial cell apoptosis in an oxidative stress-dependent fashion...
June 16, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28620099/correction-rag1-2-induces-genomic-insertions-by-mobilizing-dna-into-rag1-2-independent-breaks
#8
Philipp C Rommel, Thiago Y Oliveira, Michel C Nussenzweig, Davide F Robbiani
No abstract text is available yet for this article.
June 15, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28611158/essential-role-of-ccl21-in-establishment-of-central-self-tolerance-in-t-cells
#9
Mina Kozai, Yuki Kubo, Tomoya Katakai, Hiroyuki Kondo, Hiroshi Kiyonari, Karin Schaeuble, Sanjiv A Luther, Naozumi Ishimaru, Izumi Ohigashi, Yousuke Takahama
The chemokine receptor CCR7 directs T cell relocation into and within lymphoid organs, including the migration of developing thymocytes into the thymic medulla. However, how three functional CCR7 ligands in mouse, CCL19, CCL21Ser, and CCL21Leu, divide their roles in immune organs is unclear. By producing mice specifically deficient in CCL21Ser, we show that CCL21Ser is essential for the accumulation of positively selected thymocytes in the thymic medulla. CCL21Ser-deficient mice were impaired in the medullary deletion of self-reactive thymocytes and developed autoimmune dacryoadenitis...
June 13, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28606989/tlr7-8-activation-in-neutrophils-impairs-immune-complex-phagocytosis-through-shedding-of-fcgriia
#10
Christian Lood, Sabine Arve, Jeffrey Ledbetter, Keith B Elkon
Neutrophils play a crucial role in host defense. However, neutrophil activation is also linked to autoimmune diseases such as systemic lupus erythematosus (SLE), where nucleic acid-containing immune complexes (IC) drive inflammation. The role of Toll-like receptor (TLR) signaling in processing of SLE ICs and downstream inflammatory neutrophil effector functions is not known. We observed that TLR7/8 activation leads to a furin-dependent proteolytic cleavage of the N-terminal part of FcgRIIA, shifting neutrophils away from phagocytosis of ICs toward the programmed form of necrosis, NETosis...
June 12, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28606988/recurrent-rhinovirus-infections-in-a-child-with-inherited-mda5-deficiency
#11
Ian T Lamborn, Huie Jing, Yu Zhang, Scott B Drutman, Jordan K Abbott, Shirin Munir, Sangeeta Bade, Heardley M Murdock, Celia P Santos, Linda G Brock, Evan Masutani, Emmanuel Y Fordjour, Joshua J McElwee, Jason D Hughes, Dave P Nichols, Aziz Belkadi, Andrew J Oler, Corinne S Happel, Helen F Matthews, Laurent Abel, Peter L Collins, Kanta Subbarao, Erwin W Gelfand, Michael J Ciancanelli, Jean-Laurent Casanova, Helen C Su
MDA5 is a cytosolic sensor of double-stranded RNA (ds)RNA including viral byproducts and intermediates. We studied a child with life-threatening, recurrent respiratory tract infections, caused by viruses including human rhinovirus (HRV), influenza virus, and respiratory syncytial virus (RSV). We identified in her a homozygous missense mutation in IFIH1 that encodes MDA5. Mutant MDA5 was expressed but did not recognize the synthetic MDA5 agonist/(ds)RNA mimic polyinosinic-polycytidylic acid. When overexpressed, mutant MDA5 failed to drive luciferase activity from the IFNB1 promoter or promoters containing ISRE or NF-κB sequence motifs...
June 12, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28606987/the-fate-and-lifespan-of-human-monocyte-subsets-in-steady-state-and-systemic-inflammation
#12
Amit A Patel, Yan Zhang, James N Fullerton, Lies Boelen, Anthony Rongvaux, Alexander A Maini, Venetia Bigley, Richard A Flavell, Derek W Gilroy, Becca Asquith, Derek Macallan, Simon Yona
In humans, the monocyte pool comprises three subsets (classical, intermediate, and nonclassical) that circulate in dynamic equilibrium. The kinetics underlying their generation, differentiation, and disappearance are critical to understanding both steady-state homeostasis and inflammatory responses. Here, using human in vivo deuterium labeling, we demonstrate that classical monocytes emerge first from marrow, after a postmitotic interval of 1.6 d, and circulate for a day. Subsequent labeling of intermediate and nonclassical monocytes is consistent with a model of sequential transition...
June 12, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28600438/human-rela-haploinsufficiency-results-in-autosomal-dominant-chronic-mucocutaneous-ulceration
#13
Yousef R Badran, Fatma Dedeoglu, Juan Manuel Leyva Castillo, Wayne Bainter, Toshiro K Ohsumi, Athos Bousvaros, Jeffrey D Goldsmith, Raif S Geha, Janet Chou
The treatment of chronic mucocutaneous ulceration is challenging, and only some patients respond selectively to inhibitors of tumor necrosis factor-α (TNF). TNF activates opposing pathways leading to caspase-8-mediated apoptosis as well as nuclear factor κB (NF-κB)-dependent cell survival. We investigated the etiology of autosomal-dominant, mucocutaneous ulceration in a family whose proband was dependent on anti-TNF therapy for sustained remission. A heterozygous mutation in RELA, encoding the NF-κB subunit RelA, segregated with the disease phenotype and resulted in RelA haploinsufficiency...
June 9, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28588016/commensal-microbes-provide-first-line-defense-against-listeria-monocytogenes-infection
#14
Simone Becattini, Eric R Littmann, Rebecca A Carter, Sohn G Kim, Sejal M Morjaria, Lilan Ling, Yangtsho Gyaltshen, Emily Fontana, Ying Taur, Ingrid M Leiner, Eric G Pamer
Listeria monocytogenes is a foodborne pathogen that causes septicemia, meningitis and chorioamnionitis and is associated with high mortality. Immunocompetent humans and animals, however, can tolerate high doses of L. monocytogenes without developing systemic disease. The intestinal microbiota provides colonization resistance against many orally acquired pathogens, and antibiotic-mediated depletion of the microbiota reduces host resistance to infection. Here we show that a diverse microbiota markedly reduces Listeria monocytogenes colonization of the gut lumen and prevents systemic dissemination...
June 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28572216/genetic-subclone-architecture-of-tumor-clone-initiating-cells-in-colorectal-cancer
#15
Klara M Giessler, Kortine Kleinheinz, Daniel Huebschmann, Gnana Prakash Balasubramanian, Taronish D Dubash, Sebastian M Dieter, Christine Siegl, Friederike Herbst, Sarah Weber, Christopher M Hoffmann, Raffaele Fronza, Ivo Buchhalter, Nagarajan Paramasivam, Roland Eils, Manfred Schmidt, Christof von Kalle, Martin Schneider, Alexis Ulrich, Claudia Scholl, Stefan Fröhling, Wilko Weichert, Benedikt Brors, Matthias Schlesner, Claudia R Ball, Hanno Glimm
A hierarchically organized cell compartment drives colorectal cancer (CRC) progression. Genetic barcoding allows monitoring of the clonal output of tumorigenic cells without prospective isolation. In this study, we asked whether tumor clone-initiating cells (TcICs) were genetically heterogeneous and whether differences in self-renewal and activation reflected differential kinetics among individual subclones or functional hierarchies within subclones. Monitoring genomic subclone kinetics in three patient tumors and corresponding serial xenografts and spheroids by high-coverage whole-genome sequencing, clustering of genetic aberrations, subclone combinatorics, and mutational signature analysis revealed at least two to four genetic subclones per sample...
June 1, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28572215/correction-early-onset-combined-immunodeficiency-and-autoimmunity-in-patients-with-loss-of-function-mutation-in-lat
#16
Baerbel Keller, Irina Zaidman, O Sascha Yousefi, Dov Hershkovitz, Jerry Stein, Susanne Unger, Kristina Schachtrup, Mikael Sigvardsson, Amir A Kuperman, Avraham Shaag, Wolfgang W Schamel, Orly Elpeleg, Klaus Warnatz, Polina Stepensky
No abstract text is available yet for this article.
June 1, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28566277/enzymatic-lipid-oxidation-by-eosinophils-propagates-coagulation-hemostasis-and-thrombotic-disease
#17
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
Blood coagulation is essential for physiological hemostasis but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of coagulation are still incompletely understood. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an independent and predictive risk factor for thrombotic events in humans...
May 31, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28566276/fra-2-regulates-b-cell-development-by-enhancing-irf4-and-foxo1-transcription
#18
Kenia Ubieta, Mireia Garcia, Bettina Grötsch, Steffen Uebe, Georg F Weber, Merle Stein, Arif Ekici, Georg Schett, Dirk Mielenz, Aline Bozec
The role of AP-1 transcription factors in early B cell development and function is still incompletely characterized. Here we address the role of Fra-2 in B cell differentiation. Deletion of Fra-2 leads to impaired B cell proliferation in the bone marrow. In addition, IL-7-stimulated pro-B cell cultures revealed a reduced differentiation from large pre-B cells to small B cells and immature B cells. Gene profiling and chromatin immunoprecipitation sequencing analyses unraveled a transcriptional reduction of the transcription factors Foxo1, Irf4, Ikaros, and Aiolos in Fra-2-deficient B cells...
May 31, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28566275/fibroblast-adapted-human-cmv-vaccines-elicit-predominantly-conventional-cd8-t-cell-responses-in-humans
#19
Susan E Murray, Pavlo A Nesterenko, Adam L Vanarsdall, Michael W Munks, Savannah M Smart, Eren M Veziroglu, Lavinia C Sagario, Ronzo Lee, Frans H J Claas, Ilias I N Doxiadis, Michael A McVoy, Stuart P Adler, Ann B Hill
Cytomegalovirus (CMV)-based vaccines have shown remarkable efficacy in the rhesus macaque model of acquired immune deficiency syndrome, enabling 50% of vaccinated monkeys to clear a subsequent virulent simian immunodeficiency virus challenge. The protective vaccine elicited unconventional CD8 T cell responses that were entirely restricted by MHC II or the nonclassical MHC I molecule, MHC-E. These unconventional responses were only elicited by a fibroblast-adapted rhesus CMV vector with limited tissue tropism; a repaired vector with normal tropism elicited conventional responses...
May 31, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28559244/gene-silencing-and-a-novel-monoallelic-expression-pattern-in-distinct-cd177-neutrophil-subsets
#20
Claudia Eulenberg-Gustavus, Sylvia Bähring, Philipp G Maass, Friedrich C Luft, Ralph Kettritz
CD177 presents antigens in allo- and autoimmune diseases on the neutrophil surface. Individuals can be either CD177-deficient or harbor distinct CD177(neg) and CD177(pos) neutrophil subsets. We studied mechanisms controlling subset-restricted CD177 expression in bimodal individuals. CD177(pos), but not CD177(neg) neutrophils, produced CD177 protein and mRNA. Haplotype analysis indicated a unique monoallelic CD177 expression pattern, where the offspring stably transcribed either the maternal or paternal allele...
May 30, 2017: Journal of Experimental Medicine
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