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June 2018 | Volume 215, No. 6

News

  • Insights

    • Less cholesterol means better tumor killing for cytotoxic T9 cells
      Less cholesterol means better tumor killing for cytotoxic T9 cells

      Ma et al. show that removal of cholesterol from CD8 T cells during type 9 differentiation increases their IL-9 production, persistence in vivo, and cytolytic function against tumors by preventing SUMOylation of liver X receptors.

      Brad Griesenauer, Sophie Paczesny

Research Articles

  • Brief Definitive Reports

    • Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression
      Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression

      Intestinal macrophages represent the last tissue macrophages thought to entirely adhere to van Furth's decades-old continuous monocyte replenishment model. In this study, Shaw et al. identify a population of intestinal macrophages that are long lived and maintained independently of monocyte replenishment over long periods of time.

      Tovah N. Shaw, Stephanie A. Houston, Kelly Wemyss, Hayley M. Bridgeman, Thomas A. Barbera, Tamsin Zangerle-Murray, Patrick Strangward, Amanda J.L. Ridley, Ping Wang, Samira Tamoutounour, Judith E. Allen, Joanne E. Konkel, John R. Grainger
    • GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever
      GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever

      Inflammasomes promote interleukin (IL)-1β secretion and pyroptosis. Kanneganti et al. now show that the pyroptosis effector gasdermin D (GSDMD) is required for systemic IL-1β secretion and autoinflammatory pathology in a mouse model of Familial Mediterranean Fever (FMF), suggesting GSDMD inhibitors as potential antiinflammatory treatments.

      Apurva Kanneganti, R.K. Subbarao Malireddi, Pedro H.V. Saavedra, Lieselotte Vande Walle, Hanne Van Gorp, Hiroto Kambara, Heather Tillman, Peter Vogel, Hongbo R. Luo, Ramnik J. Xavier, Hongbo Chi, Mohamed Lamkanfi
    • Spatial distribution and function of T follicular regulatory cells in human lymph nodes
      Spatial distribution and function of T follicular regulatory cells in human lymph nodes

      Sayin et al. describe the spatial distribution and functional characteristics of T follicular regulatory (Tfr) cells in human lymph nodes. Contrary to existing paradigms, Tfr-mediated suppression appears to be most efficient at the T-B border and within the follicle, not in the germinal center.

      Ismail Sayin, Andrea J. Radtke, Laura A. Vella, Wenjie Jin, E. John Wherry, Marcus Buggert, Michael R. Betts, Ramin S. Herati, Ronald N. Germain, David H. Canaday
    • Autism-associated neuroligin-4 mutation selectively impairs glycinergic synaptic transmission in mouse brainstem synapses
      Autism-associated neuroligin-4 mutation selectively impairs glycinergic synaptic transmission in mouse brainstem synapses

      Loss-of-function mutations of the human postsynaptic cell-adhesion protein neuroligin-4 have been repeatedly associated with autism, but the precise synaptic function of neuroligin-4 that may account for its role in autism remains unclear. Here, we show in murine brainstem synapses that neuroligin-4 is selectively required for glycinergic synaptic transmission in mice.

      Bo Zhang, Ozgun Gokce, W. Dylan Hale, Nils Brose, Thomas C. Südhof
  • Articles

    • Cholesterol negatively regulates IL-9–producing CD8<sup>+</sup> T cell differentiation and antitumor activity
      Cholesterol negatively regulates IL-9–producing CD8+ T cell differentiation and antitumor activity

      CD8+ T cells can be polarized into IL-9–secreting (Tc9) cells. Ma et al. show that Tc9 cell differentiation is associated with a low cholesterol reprogramming profile, and manipulating cholesterol content in polarizing Tc9 cells significantly affects Tc9 differentiation and antitumor response.

      Xingzhe Ma, Enguang Bi, Chunjian Huang, Yong Lu, Gang Xue, Xing Guo, Aibo Wang, Maojie Yang, Jianfei Qian, Chen Dong, Qing Yi
    • Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses
      Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses

      Pardi and colleagues report on a vaccine platform in which purified, antigen-encoding, nucleoside-modified mRNA is encapsulated in lipid nanoparticles. Immunization with this vaccine elicits potent T follicular helper cell, germinal center B cell, and protective, neutralizing antibody responses.

      Norbert Pardi, Michael J. Hogan, Martin S. Naradikian, Kaela Parkhouse, Derek W. Cain, Letitia Jones, M. Anthony Moody, Hans P. Verkerke, Arpita Myles, Elinor Willis, Celia C. LaBranche, David C. Montefiori, Jenna L. Lobby, Kevin O. Saunders, Hua-Xin Liao, Bette T. Korber, Laura L. Sutherland, Richard M. Scearce, Peter T. Hraber, István Tombácz, Hiromi Muramatsu, Houping Ni, Daniel A. Balikov, Charles Li, Barbara L. Mui, Ying K. Tam, Florian Krammer, Katalin Karikó, Patricia Polacino, Laurence C. Eisenlohr, Thomas D. Madden, Michael J. Hope, Mark G. Lewis, Kelly K. Lee, Shiu-Lok Hu, Scott E. Hensley, Michael P. Cancro, Barton F. Haynes, Drew Weissman
    • Distinct, IgG1-driven antibody response landscapes demarcate individuals with broadly HIV-1 neutralizing activity
      Distinct, IgG1-driven antibody response landscapes demarcate individuals with broadly HIV-1 neutralizing activity

      Kadelka et al. show that parameters linked with HIV-1 broadly neutralizing antibody (bnAb) development shape HIV-1–binding antibody responses in an antigen and IgG subclass dependent manner. Identified HIV-1 antibody signature landscapes reveal a shift toward IgG1-driven responses in bnAb developers.

      Claus Kadelka, Thomas Liechti, Hanna Ebner, Merle Schanz, Peter Rusert, Nikolas Friedrich, Emanuel Stiegeler, Dominique L. Braun, Michael Huber, Alexandra U. Scherrer, Jacqueline Weber, Therese Uhr, Herbert Kuster, Benjamin Misselwitz, Matthias Cavassini, Enos Bernasconi, Matthias Hoffmann, Alexandra Calmy, Manuel Battegay, Andri Rauch, Sabine Yerly, Vincent Aubert, Thomas Klimkait, Jürg Böni, Roger D. Kouyos, Huldrych F. Günthard, Alexandra Trkola, the Swiss HIV Cohort Study
    • Peripheral PDGFRα<sup>+</sup>gp38<sup>+</sup> mesenchymal cells support the differentiation of fetal liver–derived ILC2
      Peripheral PDGFRα+gp38+ mesenchymal cells support the differentiation of fetal liver–derived ILC2

      We demonstrate that the quantity of IL-7 and Notch signaling differentially regulate lymphocyte fate. We also identify ILC progenitor and immature ILC2 in the fetal mesentery, which are terminally differentiated and matured by PDGFRα+gp38+ mesenchymal cells.

      Satoshi Koga, Katsuto Hozumi, Ken-ichi Hirano, Masaki Yazawa, Tommy Terooatea, Aki Minoda, Takashi Nagasawa, Shigeo Koyasu, Kazuyo Moro
    • Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia
      Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia

      Peripherally derived macrophages can engraft the brain in the context of chronic microglia loss without brain irradiation and maintain a unique transcriptional signature throughout different experimental contexts.

      James C. Cronk, Anthony J. Filiano, Antoine Louveau, Ioana Marin, Rachel Marsh, Emily Ji, Dylan H. Goldman, Igor Smirnov, Nicholas Geraci, Scott Acton, Christopher C. Overall, Jonathan Kipnis
    • P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer’s disease model
      P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer’s disease model

      Reichenbach et al. show that long-term P2Y1-receptor inhibition normalizes cerebral network dysfunction in an Alzheimer’s disease mouse model. This network recovery restores functional and structural synaptic integrity as well as learning and memory, establishing P2Y1-receptor inhibition as a novel potential treatment target.

      Nicole Reichenbach, Andrea Delekate, Björn Breithausen, Kevin Keppler, Stefanie Poll, Theresa Schulte, Jan Peter, Monika Plescher, Jan N. Hansen, Nelli Blank, Armin Keller, Martin Fuhrmann, Christian Henneberger, Annett Halle, Gabor C. Petzold
    • Inhibition of PKCδ reduces amyloid-β levels and reverses Alzheimer disease phenotypes
      Inhibition of PKCδ reduces amyloid-β levels and reverses Alzheimer disease phenotypes

      Du et al. demonstrate that PKCδ modulates BACE1 expression and amyloidogenic amyloid precursor protein processing. Inhibition of PKCδ markedly reduces BACE1 expression, β-amyloid levels, and amyloid plaque formation and also rescues cognitive deficits in Alzheimer disease mouse models.

      Ying Du, Yingjun Zhao, Chuan Li, Qiuyang Zheng, Jing Tian, Zhuyi Li, Timothy Y. Huang, Wei Zhang, Huaxi Xu
    • Inhibition of UGT8 suppresses basal-like breast cancer progression by attenuating sulfatide–αVβ5 axis
      Inhibition of UGT8 suppresses basal-like breast cancer progression by attenuating sulfatide–αVβ5 axis

      Cao et al. show that UGT8 promotes BLBC progression through activating sulfatide–αVβ5 axis. ZA is identified as a direct inhibitor of UGT8 and suppresses BLBC progression, suggesting that inhibition of UGT8 offers a promising opportunity for treating BLBC.

      Qianhua Cao, Xingyu Chen, Xuebiao Wu, Ruocen Liao, Panpan Huang, Yanjia Tan, Li Wang, Guoping Ren, Jian Huang, Chenfang Dong
    • Targeting tumor cell plasticity by combined inhibition of NOTCH and MAPK signaling in colon cancer
      Targeting tumor cell plasticity by combined inhibition of NOTCH and MAPK signaling in colon cancer

      Schmidt et al. propose a new concept for colon cancer therapy that advocates specific and simultaneous targeting of different tumor cell subpopulations with high NOTCH- and MAPK-signaling pathway activity. This overcomes treatment resistance by tumor cell plasticity and strongly improves therapy response.

      Eva Marina Schmidt, Sebastian Lamprecht, Cristina Blaj, Christian Schaaf, Stefan Krebs, Helmut Blum, Heiko Hermeking, Andreas Jung, Thomas Kirchner, David Horst
    • IL1RAP potentiates multiple oncogenic signaling pathways in AML
      IL1RAP potentiates multiple oncogenic signaling pathways in AML

      IL1RAP is an emerging target for AML therapy. Studying its cell-intrinsic function revealed that IL1RAP interacts with and amplifies signaling through c-KIT and FLT3 in AML cells. This novel promiscuous role of IL1RAP in AML has implications for therapeutic targeting.

      Kelly Mitchell, Laura Barreyro, Tihomira I. Todorova, Samuel J. Taylor, Iléana Antony-Debré, Swathi-Rao Narayanagari, Luis A. Carvajal, Joana Leite, Zubair Piperdi, Gopichand Pendurti, Ioannis Mantzaris, Elisabeth Paietta, Amit Verma, Kira Gritsman, Ulrich Steidl
    • Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation
      Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation

      Nagase and Inoue et al. generated a novel Asxl1 mutant mouse model to mimic clonal hematopoiesis and myelodysplastic syndromes caused by ASXL1 mutations and elucidated the effects of mutant versus wild-type ASXL1 on hematopoiesis, gene expression, and chromatin state.

      Reina Nagase, Daichi Inoue, Alessandro Pastore, Takeshi Fujino, Hsin-An Hou, Norimasa Yamasaki, Susumu Goyama, Makoto Saika, Akinori Kanai, Yasuyuki Sera, Sayuri Horikawa, Yasunori Ota, Shuhei Asada, Yasutaka Hayashi, Kimihito Cojin Kawabata, Reina Takeda, Hwei-Fang Tien, Hiroaki Honda, Omar Abdel-Wahab, Toshio Kitamura
    • <em>PTEN</em> deletion in luminal cells of mature prostate induces replication stress and senescence in vivo
      PTEN deletion in luminal cells of mature prostate induces replication stress and senescence in vivo

      Parisotto et al. demonstrate that ablation of the tumor suppressor gene PTEN in prostatic luminal epithelial cells of adult mice stimulates their proliferation, induces replication stress and a DNA damage response, followed by growth arrest with characteristics of cell senescence.

      Maxime Parisotto, Elise Grelet, Rana El Bizri, Yongyuan Dai, Julie Terzic, Doriane Eckert, Laetitia Gargowitsch, Jean-Marc Bornert, Daniel Metzger

Correction

  • Correction: Peroxisome proliferator–activated receptor (PPAR)α expression in T cells mediates gender differences in development of T cell–mediated autoimmunity
    Shannon E. Dunn, Shalina S. Ousman, Raymond A. Sobel, Luis Zuniga, Sergio E. Baranzini, Sawsan Youssef, Andrea Crowell, John Loh, Jorge Oksenberg, Lawrence Steinman
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The Journal of Experimental Medicine: 215 (6)

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