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Klaus rajewsky

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https://www.readbyqxmd.com/read/27880903/mirnas-are-essential-for-the-regulation-of-the-pi3k-akt-foxo-pathway-and-receptor-editing-during-b%C3%A2-cell-maturation
#1
Maryaline Coffre, David Benhamou, David Rieß, Lili Blumenberg, Valentina Snetkova, Marcus J Hines, Tirtha Chakraborty, Sofia Bajwa, Kari Jensen, Mark M W Chong, Lelise Getu, Gregg J Silverman, Robert Blelloch, Dan R Littman, Dinis Calado, Doron Melamed, Jane A Skok, Klaus Rajewsky, Sergei B Koralov
B cell development is a tightly regulated process dependent on sequential rearrangements of immunoglobulin loci that encode the antigen receptor. To elucidate the role of microRNAs (miRNAs) in the orchestration of B cell development, we ablated all miRNAs at the earliest stage of B cell development by conditionally targeting the enzymes critical for RNAi in early B cell precursors. Absence of any one of these enzymes led to a block at the pro- to pre-B cell transition due to increased apoptosis and a failure of pre-B cells to proliferate...
November 22, 2016: Cell Reports
https://www.readbyqxmd.com/read/27856754/mouse-model-for-acute-epstein-barr-virus-infection
#2
Tristan Wirtz, Timm Weber, Sven Kracker, Thomas Sommermann, Klaus Rajewsky, Tomoharu Yasuda
Epstein-Barr Virus (EBV) infects human B cells and drives them into continuous proliferation. Two key viral factors in this process are the latent membrane proteins LMP1 and LMP2A, which mimic constitutively activated CD40 receptor and B-cell receptor signaling, respectively. EBV-infected B cells elicit a powerful T-cell response that clears the infected B cells and leads to life-long immunity. Insufficient immune surveillance of EBV-infected B cells causes life-threatening lymphoproliferative disorders, including mostly germinal center (GC)-derived B-cell lymphomas...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27729526/efficient-crispr-mediated-mutagenesis-in-primary-immune-cells-using-crisprgold-and-a-c57bl-6-cas9-transgenic-mouse-line
#3
Van Trung Chu, Robin Graf, Tristan Wirtz, Timm Weber, Jeremy Favret, Xun Li, Kerstin Petsch, Ngoc Tung Tran, Michael H Sieweke, Claudia Berek, Ralf Kühn, Klaus Rajewsky
Applying clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9)-mediated mutagenesis to primary mouse immune cells, we used high-fidelity single guide RNAs (sgRNAs) designed with an sgRNA design tool (CrispRGold) to target genes in primary B cells, T cells, and macrophages isolated from a Cas9 transgenic mouse line. Using this system, we achieved an average knockout efficiency of 80% in B cells. On this basis, we established a robust small-scale CRISPR-mediated screen in these cells and identified genes essential for B-cell activation and plasma cell differentiation...
November 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27346348/a-c-myc-mir17-92-pten-axis-controls-pi3k-mediated-positive-and-negative-selection-in-b-cell-development-and-reconstitutes-cd19-deficiency
#4
David Benhamou, Verena Labi, Rostislav Novak, Isabelle Dai, Shani Shafir-Alon, Ariel Weiss, Renaud Gaujoux, Rüdiger Arnold, Shai S Shen-Orr, Klaus Rajewsky, Doron Melamed
PI3K activity determines positive and negative selection of B cells, a key process for immune tolerance and B cell maturation. Activation of PI3K is balanced by phosphatase and tensin homolog (Pten), the PI3K's main antagonistic phosphatase. Yet, the extent of feedback regulation between PI3K activity and Pten expression during B cell development is unclear. Here, we show that PI3K control of this process is achieved post-transcriptionally by an axis composed of a transcription factor (c-Myc), a microRNA (miR17-92), and Pten...
July 12, 2016: Cell Reports
https://www.readbyqxmd.com/read/27153500/mir-150-controls-b-cell-differentiation-by-targeting-the-transcription-factor-c-myb
#5
Changchun Xiao, Dinis Pedro Calado, Gunther Galler, To-Ha Thai, Heide Christine Patterson, Jing Wang, Nikolaus Rajewsky, Timothy P Bender, Klaus Rajewsky
No abstract text is available yet for this article.
May 5, 2016: Cell
https://www.readbyqxmd.com/read/27099294/canonical-nf-%C3%AE%C2%BAb-signaling-is-uniquely-required-for-the-long-term-persistence-of-functional-mature-b-cells
#6
Emmanuel Derudder, Sebastian Herzog, Verena Labi, Tomoharu Yasuda, Karl Köchert, Martin Janz, Andreas Villunger, Marc Schmidt-Supprian, Klaus Rajewsky
Although canonical NF-κB signaling is crucial to generate a normal mature B-cell compartment, its role in the persistence of resting mature B cells is controversial. To resolve this conflict, we ablated NF-κB essential modulator (NEMO) and IκB kinase 2 (IKK2), two essential mediators of the canonical pathway, either early on in B-cell development or specifically in mature B cells. Early ablation severely inhibited the generation of all mature B-cell subsets, but follicular B-cell numbers could be largely rescued by ectopic expression of B-cell lymphoma 2 (Bcl2), despite a persisting block at the transitional stage...
May 3, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27091986/tissue-specific-dna-demethylation-is-required-for-proper-b-cell-differentiation-and-function
#7
Shari Orlanski, Verena Labi, Yitzhak Reizel, Adam Spiro, Michal Lichtenstein, Rena Levin-Klein, Sergei B Koralov, Yael Skversky, Klaus Rajewsky, Howard Cedar, Yehudit Bergman
There is ample evidence that somatic cell differentiation during development is accompanied by extensive DNA demethylation of specific sites that vary between cell types. Although the mechanism of this process has not yet been elucidated, it is likely to involve the conversion of 5mC to 5hmC by Tet enzymes. We show that a Tet2/Tet3 conditional knockout at early stages of B-cell development largely prevents lineage-specific programmed demethylation events. This lack of demethylation affects the expression of nearby B-cell lineage genes by impairing enhancer activity, thus causing defects in B-cell differentiation and function...
May 3, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26843325/survival-of-ig%C3%AE-deficient-mature-b-cells-requires-baff-r-function
#8
Ella Levit-Zerdoun, Martin Becker, Roland Pohlmeyer, Isabel Wilhelm, Palash Chandra Maity, Klaus Rajewsky, Michael Reth, Elias Hobeika
Expression of a functional BCR is essential for the development of mature B cells and has been invoked in the control of their maintenance. To test this maintenance function in a new experimental setting, we used the tamoxifen-inducible mb1-CreER(T2) mouse strain to delete or truncate either the mb-1 gene encoding the BCR signaling subunit Igα or the VDJ segment of the IgH (H chain [HC]). In this system, Cre-mediated deletion of the mb-1 gene is accompanied by expression of a GFP reporter. We found that, although the Igα-deficient mature B cells survive for >20 d in vivo, the HC-deficient or Igα tail-truncated B cell population is short-lived, with the HC-deficient cells displaying signs of an unfolded protein response...
March 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/26834155/mir-23%C3%A2-27%C3%A2-24-clusters-control-effector-t-cell-differentiation-and-function
#9
Sunglim Cho, Cheng-Jang Wu, Tomoharu Yasuda, Leilani O Cruz, Aly Azeem Khan, Ling-Li Lin, Duc T Nguyen, Marina Miller, Hyang-Mi Lee, Ming-Ling Kuo, David H Broide, Klaus Rajewsky, Alexander Y Rudensky, Li-Fan Lu
Coordinated repression of gene expression by evolutionarily conserved microRNA (miRNA) clusters and paralogs ensures that miRNAs efficiently exert their biological impact. Combining both loss- and gain-of-function genetic approaches, we show that the miR-23∼27∼24 clusters regulate multiple aspects of T cell biology, particularly helper T (Th) 2 immunity. Low expression of this miRNA family confers proper effector T cell function at both physiological and pathological settings. Further studies in T cells with exaggerated regulation by individual members of the miR-23∼27∼24 clusters revealed that miR-24 and miR-27 collaboratively limit Th2 responses through targeting IL-4 and GATA3 in both direct and indirect manners...
February 8, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/26831526/immunological-memory-lessons-from-the-past-and-a-look-to-the-future
#10
Donna L Farber, Mihai G Netea, Andreas Radbruch, Klaus Rajewsky, Rolf M Zinkernagel
Immunological memory is considered to be one of the cardinal features of the adaptive immune system. Despite being a recognized phenomenon since the time of the ancient Greeks, immunologists are yet to fully appreciate the mechanisms that control memory responses in the immune system. Furthermore, our definition of immunological memory itself continues to evolve, with recent suggestions that innate immune cells also show memory-like behaviour. In this Viewpoint article, Nature Reviews Immunology invites five leading immunologists to share their thoughts on our current understanding of the nature of immunological memory...
February 2016: Nature Reviews. Immunology
https://www.readbyqxmd.com/read/26772810/efficient-generation-of-rosa26-knock-in-mice-using-crispr-cas9-in-c57bl-6-zygotes
#11
Van Trung Chu, Timm Weber, Robin Graf, Thomas Sommermann, Kerstin Petsch, Ulrike Sack, Pavel Volchkov, Klaus Rajewsky, Ralf Kühn
BACKGROUND: The CRISPR/Cas9 system is increasingly used for gene inactivation in mouse zygotes, but homology-directed mutagenesis and use of inbred embryos are less established. In particular, Rosa26 knock-in alleles for the insertion of transgenes in a genomic 'safe harbor' site, have not been produced. Here we applied CRISPR/Cas9 for the knock-in of 8-11 kb inserts into Rosa26 of C57BL/6 zygotes. RESULTS: We found that 10-20 % of live pups derived from microinjected zygotes were founder mutants, without apparent off-target effects, and up to 50 % knock-in embryos were recovered upon coinjection of Cas9 mRNA and protein...
2016: BMC Biotechnology
https://www.readbyqxmd.com/read/26735015/foxo1-couples-metabolic-activity-and-growth-state-in-the-vascular-endothelium
#12
Kerstin Wilhelm, Katharina Happel, Guy Eelen, Sandra Schoors, Mark F Oellerich, Radiance Lim, Barbara Zimmermann, Irene M Aspalter, Claudio A Franco, Thomas Boettger, Thomas Braun, Marcus Fruttiger, Klaus Rajewsky, Charles Keller, Jens C Brüning, Holger Gerhardt, Peter Carmeliet, Michael Potente
Endothelial cells (ECs) are plastic cells that can switch between growth states with different bioenergetic and biosynthetic requirements. Although quiescent in most healthy tissues, ECs divide and migrate rapidly upon proangiogenic stimulation. Adjusting endothelial metabolism to the growth state is central to normal vessel growth and function, yet it is poorly understood at the molecular level. Here we report that the forkhead box O (FOXO) transcription factor FOXO1 is an essential regulator of vascular growth that couples metabolic and proliferative activities in ECs...
January 14, 2016: Nature
https://www.readbyqxmd.com/read/26620760/pi3-kinase-and-foxo1-transcription-factor-activity-differentially-control-b-cells-in-the-germinal-center-light-and-dark-zones
#13
Sandrine Sander, Van Trung Chu, Tomoharu Yasuda, Andrew Franklin, Robin Graf, Dinis Pedro Calado, Shuang Li, Koshi Imami, Matthias Selbach, Michela Di Virgilio, Lars Bullinger, Klaus Rajewsky
Phosphatidylinositol 3' OH kinase (PI3K) signaling and FOXO transcription factors play opposing roles at several B cell developmental stages. We show here abundant nuclear FOXO1 expression in the proliferative compartment of the germinal center (GC), its dark zone (DZ), and PI3K activity, downregulating FOXO1, in the light zone (LZ), where cells are selected for further differentiation. In the LZ, however, FOXO1 was expressed in a fraction of cells destined for DZ reentry. Upon FOXO1 ablation or induction of PI3K activity, GCs lost their DZ, owing at least partly to downregulation of the chemokine receptor CXCR4...
December 15, 2015: Immunity
https://www.readbyqxmd.com/read/26456821/gab1-and-mapk-signaling-are-essential-in-the-hair-cycle-and-hair-follicle-stem-cell-quiescence
#14
Özlem Akilli Öztürk, Hubert Pakula, Jolanta Chmielowiec, Jingjing Qi, Simone Stein, Linxiang Lan, Yoshiteru Sasaki, Klaus Rajewsky, Walter Birchmeier
Gab1 is a scaffold protein that acts downstream of receptor tyrosine kinases. Here, we produced conditional Gab1 mutant mice (by K14- and Krox20-cre) and show that Gab1 mediates crucial signals in the control of both the hair cycle and the self-renewal of hair follicle stem cells. Remarkably, mutant hair follicles do not enter catagen, the destructive phase of the hair cycle. Instead, hair follicle stem cells lose quiescence and become exhausted, and thus no stem cell niches are established in the bulges. Moreover, conditional sustained activation of Mapk signaling by expression of a gain-of-function Mek1(DD) allele (by Krox20-cre) rescues hair cycle deficits and restores quiescence of the stem cells...
October 20, 2015: Cell Reports
https://www.readbyqxmd.com/read/26371314/the-b-cell-antigen-receptor-integrates-adaptive-and-innate-immune-signals
#15
Kevin L Otipoby, Ari Waisman, Emmanuel Derudder, Lakshmi Srinivasan, Andrew Franklin, Klaus Rajewsky
B cells respond to antigens by engagement of their B-cell antigen receptor (BCR) and of coreceptors through which signals from helper T cells or pathogen-associated molecular patterns are delivered. We show that the proliferative response of B cells to the latter stimuli is controlled by BCR-dependent activation of phosphoinositidyl 3-kinase (PI-3K) signaling. Glycogen synthase kinase 3β and Foxo1 are two PI-3K-regulated targets that play important roles, but to different extents, depending on the specific mitogen...
September 29, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26096553/layered-evolution-in-the-immune-system-a-view-from-history
#16
REVIEW
Leonore A Herzenberg
Although much had still to be learned, evidence indicating that B-1a lymphocytes very likely belonged to a distinct lineage was largely in place by the time of the first large B-1a conference in 1991. The widely respected group of immunologists attending that meeting (including Tasuko Honjo and Klaus Rajewsky) developed and ultimately published the B-1a notation still in use today. Here, I briefly review some of the early B-1a findings that underlie current studies. I close with a brief summary of recent studies, mainly from my laboratory, showing that the hematopoietic stem cell (HSC) we all know and love as the origin of the cells that populate the adult lymphoid and myeloid system today is nonetheless not the origin of the B-1a lymphocytes with which most of us work today...
December 2015: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/25934172/a-rapid-embryonic-stem-cell-based-mouse-model-for-b-cell-lymphomas-driven-by-epstein-barr-virus-protein-lmp1
#17
Zhaoqing Ba, Fei-Long Meng, Monica Gostissa, Pei-Yi Huang, Qiang Ke, Zhe Wang, Mai N Dao, Yuko Fujiwara, Klaus Rajewsky, Baochun Zhang, Frederick W Alt
The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) contributes to oncogenic human B-cell transformation. Mouse B cells conditionally expressing LMP1 are not predisposed to B-cell malignancies, as LMP1-expressing B cells are eliminated by T cells. However, mice with conditional B-cell LMP1 expression and genetic elimination of α/β and γ/δ T cells ("CLT" mice) die early in association with B-cell lymphoproliferation and lymphomagenesis. Generation of CLT mice involves in-breeding multiple independently segregating alleles...
June 2015: Cancer Immunology Research
https://www.readbyqxmd.com/read/25921526/an-oncogenic-role-for-alternative-nf-%C3%AE%C2%BAb-signaling-in-dlbcl-revealed-upon-deregulated-bcl6-expression
#18
Baochun Zhang, Dinis Pedro Calado, Zhe Wang, Sebastian Fröhler, Karl Köchert, Yu Qian, Sergei B Koralov, Marc Schmidt-Supprian, Yoshiteru Sasaki, Christine Unitt, Scott Rodig, Wei Chen, Riccardo Dalla-Favera, Frederick W Alt, Laura Pasqualucci, Klaus Rajewsky
Diffuse large B cell lymphoma (DLBCL) is a complex disease comprising diverse subtypes and genetic profiles. Possibly because of the prevalence of genetic alterations activating canonical NF-κB activity, a role for oncogenic lesions that activate the alternative NF-κB pathway in DLBCL has remained elusive. Here, we show that deletion/mutation of TRAF3, a negative regulator of the alternative NF-κB pathway, occurs in ∼15% of DLBCLs and that it often coexists with BCL6 translocation, which prevents terminal B cell differentiation...
May 5, 2015: Cell Reports
https://www.readbyqxmd.com/read/25912787/the-herzenberg-lecture-how-to-make-a-b-1-cell
#19
Klaus Rajewsky
This essay presents a short historical perspective on B-1 cells and a synopsis of contemporary work in my laboratory on generating B-1 from B-2 cells via B cell receptor exchange.
December 2015: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/25803306/increasing-the-efficiency-of-homology-directed-repair-for-crispr-cas9-induced-precise-gene-editing-in-mammalian-cells
#20
Van Trung Chu, Timm Weber, Benedikt Wefers, Wolfgang Wurst, Sandrine Sander, Klaus Rajewsky, Ralf Kühn
The insertion of precise genetic modifications by genome editing tools such as CRISPR-Cas9 is limited by the relatively low efficiency of homology-directed repair (HDR) compared with the higher efficiency of the nonhomologous end-joining (NHEJ) pathway. To enhance HDR, enabling the insertion of precise genetic modifications, we suppressed the NHEJ key molecules KU70, KU80 or DNA ligase IV by gene silencing, the ligase IV inhibitor SCR7 or the coexpression of adenovirus 4 E1B55K and E4orf6 proteins in a 'traffic light' and other reporter systems...
May 2015: Nature Biotechnology
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