DOCSLIB.ORG

An Essential Role of UBXN3B in B Lymphopoiesis Tingting Geng Et Al. This File Contains 9 Supplemental Figures and Legends

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
An Essential Role of UBXN3B in B Lymphopoiesis Tingting Geng Et Al. This File Contains 9 Supplemental Figures and Legends An Essential Role of UBXN3B in B Lymphopoiesis Tingting Geng et al. This file contains 9 supplemental figures and legends. a Viral load (relative) load Viral Serum TNF-α b +/+ Serum IL-6 Ubxn3b Ubxn3b-/- Ubxn3b+/+ 100 100 ** Ubxn3b-/- ** 10 10 IL-6 IL-6 (pg/ml) GM-CSF (pg/ml) GM-CSF 1 1 0 3 8 14 35 0 3 8 14 35 Time post infection (Days) Time post infection (Days) Serum IL-10 Serum CXCL10 Ubxn3b+/+ Ubxn3b-/- 10000 1000 +/+ -/- * Ubxn3b Ubxn3b 1000 100 IFN-γ (pg/ml) CXCL10 (pg/ml) CXCL10 100 10 0 3 8 14 35 0 3 8 14 35 Time post infection (Days) Time post infection (Days) IL-1β IL-1β (pg/ml) Supplemental Fig.s1 UBXN3B is essential for controlling SARS-CoV-2 pathogenesis. Sex- and-age matched littermates were administered 2x105 plaque forming units (PFU) of SARS-CoV-2 intranasally. a) Quantitative RT-PCR (qPCR) quantification of SARS-CoV-2 loads in the lung at days 3 and 10 post infection (p.i). Each symbol= one mouse, the small horizontal line: the median of the result. *, p<0.05; **, p<0.01, ***, p<0.001 (non-parametric Mann-Whitney test) between Ubxn3b+/+ and Ubxn3b-/- littermates at each time point. Ubxn3b+/+ Ubxn3b-/- Live Live 78.0 83.6 CD45+ CD45+ UV UV CD45 94.1 CD45 90.9 FSC-A FSC-A FSC-A FSC-A Mac Mac 23.0 38.1 MHC II MHC II CD11b Eso CD11b Eso 5.81 7.44 CD19, MHCII subset F4_80, CD11b subset CD19, MHCII subset F4_80, CD11b subset Myeloid panel Myeloid 70.1 65.6 94.2 51.1 CD19 F4/80 CD19 F4/80 Neu DC Neu DC 4.87 1.02 16.2 2.24 CD11b, Ly-6G subset CD11b, Ly-6G subset 94.9 83.3 Ly-6G Ly-6G MHC II MHC II CD11b CD11c CD11b CD11c Live Live 82.3 76.5 CD45+ CD45+ 91.1 91.3 UV UV CD45 CD45 FSC-A FSC-A FSC-A FSC-A Q1 Q2 Q1 Q2 Q1 Q2 Q1 Q2 Lymphoid panel Lymphoid 20.1 0.29 54.1 1.17 4.27 0.060 39.2 2.55 CD4 CD4 CD19 CD19 Q4 Q3 Q4 Q3 Q4 Q3 Q4 Q3 47.0 32.6 7.21 37.5 67.7 28.0 7.27 51.0 CD3 CD8 CD3 CD8 Supplemental Fig.s2 Dysregulated immune compartmentalization in Ubxn3b-/- lung. The graphs illustrate the gating strategy of different immune populations in the lung at day 35 post SARS- CoV-2 infection (related to Fig.2f,g). Mac: macrophage, Neu: neutrophil, DC: dendritic cell, Eso: eosinophil. CD3+ T, CD8+ T, CD4+ T, CD19+ B. Ubxn3b+/+ Ubxn3b-/- 40x T WP RP 200x A MZ MS MS Supplemental Fig.s3 Splenic atrophy in Ubxn3b-/- mice. The figures show H&E staining of spleens on day 35 after SARS-CoV-2 infection. The red arrow head indicates reduced cell density in the marginal zones of white pulps. The green circles likely show the myeloid clumps in red pulps. WP: white pulp, RP: red pulp, A: central arteriole, MS: marginal sinus, MZ: marginal zone, T: trabecula. Sting +/+ Sting-/- a Q1 Q2 Q1 Q2 28.1 0.38 29.4 0.62 Q4 Q3 Q4 Q3 Comp-APC-A :: CD19 Comp-APC-A :: CD19 28.9 42.7 17.2 52.8 Comp-PE-Dazzle594-A :: CD3 Comp-PE-Dazzle594-A :: CD3 Neu Neu 61.5 46.2 Blood cell Blood CD11b, Ly-6G subset CD11b, Ly-6G subset 37.6 52.5 Comp-Alexa Fluor 700-A ::Ly-6G Comp-Alexa Fluor 700-A ::Ly-6G Comp-APC-Fire750-A :: CD11b Comp-APC-Fire750-A :: CD11b Mono Mono 15.9 13.0 CD11b, CD115 subset CD11b, CD115 subset 82.9 85.6 Comp-BVio711-A ::CD115 Comp-BVio711-A ::CD115 Comp-APC-Fire750-A :: CD11b Comp-APC-Fire750-A :: CD11b b c + % of CD45 Cell counts / ml / counts Cell Supplemental Fig.s4 STING is dispensable for steady-state hematopoietic homeostasis. a) The gating strategy, b) The percentage and c) counts of each blood cell type in Sting+/+ and Sting-/- littermates, quantitated by flow cytometry. Each symbol=one animal. The horizontal line indicate the mean of the results. RBC: red blood cell, WBC: white blood cell, CD19+: B cell, CD3+ : T cell, Neu: neutrophil, Mono: monocyte. a B cell T cell Neu Mono Q1 Q2 Q1 Q2 Q1 Q2 Q1 Q2 0.015 4.51E-3 7.54 0.058 0 0 0 0 BM > WT >BM +/+ Comp-PE-A45_1:: Q4 Q3 Comp-PE-A::45_1 Q4 Q3 Comp-PE-A::45_1 Q4 Q3 Comp-PE-A45_1:: Q4 Q3 0 100.0 3.04E-3 92.4 0 100 0 100 Ubxn3b Comp-PE-Cy7-A :: 45_2 Comp-PE-Cy7-A :: 45_2 Comp-PE-Cy7-A :: 45_2 Comp-PE-Cy7-A :: 45_2 Q1 Q2 Q1 Q2 Q1 Q2 Q1 Q2 0.052 0.10 17.0 0.23 0 0 0 0.016 BM >WT BM -/- Ubxn3b Comp-PE-A45_1 :: Q4 Q3 Comp-PE-A45_1 :: Q4 Q3 Comp-PE-A45_1 :: Q4 Q3 Comp-PE-A45_1 :: Q4 Q3 0 99.8 0 82.8 0 100 0 100.0 Comp-PE-Cy7-A :: 45_2 Comp-PE-Cy7-A :: 45_2 Comp-PE-Cy7-A :: 45_2 Comp-PE-Cy7-A :: 45_2 b Q1 Q2 Neu Mono 57.0 1.17 48.3 53.6 BM > WT >BM +/+ Q4 Q3 CD11b, Ly-6G subset Comp-APC-A CD19:: 23.3 18.6 51.0 Comp-BVio711-A :: CD115 Comp-Alexa Fluor 700-A:: Ly-6G Comp-PE-Dazzle594-A :: CD3 Comp-APC-Fire750-A :: CD11b Comp-APC-Fire750-A :: CD11b Ubxn3b Q1 Q2 Neu Mono 6.26 0.17 52.7 67.2 BM >WT BM -/- Q4 Q3 CD11b, Ly-6G subset Comp-APC-A :: CD19 60.5 33.0 46.7 Comp-BVio711-A CD115:: Comp-Alexa Fluor 700-A Ly-6G:: Ubxn3b Comp-PE-Dazzle594-A :: CD3 Comp-APC-Fire750-A :: CD11b Comp-APC-Fire750-A :: CD11b Supplemental Fig.s5. UBXN3B plays a cell-intrinsic role in B lymphopoiesis. Irradiated wild type (WT, CD45.1 ) mice were transplanted with Cre+Ubxn3bf/f (CD45.2) bone marrow . The mice were then treated with tamoxifen (TMX) to delete Ubxn3b (designated Ubxn3b−/− BM–WT) or not (designated Ubxn3b+/+ BM–WT) in hematopoietic cells. a) The percentage of blood CD45.1 and CD45.2 cells 1.5 month after bone marrow transplantation (BMT). Over 99% B/Neu/Mono are CD45.2+, over 82% T cell are CD45.2+, indicating successful irradiation and reconstitution. b) The gating strategy of blood immune cells in BMT mice (related to Fig.4). B: CD19 + B cell, T : CD3+ T cell, Neu: neutrophil, Mono: monocyte. a B cell T cell Neu Mono +/+ WT BM > Ubxn3b > WTBM -/- WT BM >Ubxn3b WTBM b +/+ WT BM > Ubxn3b > WTBM -/- WT BM >Ubxn3b WTBM c WT BM→Ubxn3b−/− −/− WT BM→Ubxn3b + % of CD45 Cell counts / ml / counts Cell Supplemental Fig.s6. UBXN3B plays a cell-intrinsic role in B lymphopoiesis. Irradiated Cre+Ubxn3bf/f and Ubxn3bf/f (CD45.2) mice were transplanted with wild type (WT, CD45.1) bone marrow . The mice were then treated with tamoxifen (TMX) to delete Ubxn3b (designated WT BM–Ubxn3b−/−) or not (designated WT BM–Ubxn3b+/+) in non-hematopoietic cells. a) The blood CD45.1 and CD45.2 cells 1.5 month after bone marrow transplantation (BMT). Over 99% B/Neu/Mono are CD45.1+, over 92% T cell are CD45.1+, indicating successful irradiation and reconstitution. b) The gating strategy of blood immune cells in BMT mice. c) The count and percentage (relative to CD45+) of each blood cell type in BMT mice at 15 days after induction of Ubxn3b deletion by tamoxifen (TMX), quantitated by flow cytometry. *, P<0.05; **, P<0.01, ***, P<0.001 (two-tailed Student’s t-test). Each symbol=one animal. The horizontal line indicate the mean of the results. RBC: red blood cell, WBC: white blood cell, B: B cell, T : T cell, Neu: neutrophil, Mono: monocyte. +/+ a Ubxn3b Ubxn3b-/- CD19+ B CD19+ B 14.1 16.8 2.19 3.28 Comp-APC-A :: CD19 CD3, CD19 subset T Comp-APC-A :: CD19 CD3, CD19 subset T Comp-APC-A :: CD19 Comp-APC-A :: CD19 83.6 1.65 96.4 0.78 Comp-PE-Alexa 594-A :: CD3 Comp-APC-Cy7-A :: IgD Comp-PE-Alexa 594-A :: CD3 Comp-APC-Cy7-A :: IgD Neu Mono Neu Mono 56.3 24.1 53.8 35.2 BM Mature cell Mature BM CD11b, Ly6G subset CD11b, Ly6G subset Comp-BV711-A:: CD115 40.8 Comp-BV711-A :: CD115 42.4 Comp-Alexa Fluor 700-A :: Ly6G Comp-Alexa Fluor 700-A :: Ly6G Comp-FITC-A :: CD11b Comp-FITC-A :: CD11b Comp-FITC-A :: CD11b Comp-FITC-A :: CD11b b Ubxn3b+/+ Ubxn3b-/- B220 B220 68.8 40.5 Dump Dump Comp-FITC-A ::dump Comp-FITC-A ::dump 19.7 Comp-BV650-A :: B220 10.2 Comp-BV650-A :: B220 FSC-A FSC-A FSC-A FSC-A D-F A-C' C C' D-F A-C' C C' 76.2 23.6 4.2917.7 36.4 61.7 6.444.81 Comp-PE-A :: BP-1 A B Comp-PE-A BP-1:: A B Comp-BV650-A :: B220 44.5 31.9 Comp-BV650-A :: B220 69.6 17.6 BM Blinage BM cell Comp-APC-A :: CD43 Comp-PerCP-Cy5-5-A :: CD24 Comp-APC-A :: CD43 Comp-PerCP-Cy5-5-A :: CD24 E F E F 24.1 19.2 Pre-Pro B 19.3 14.9 Pre-Pro B 25.6 40.1 D D Comp-BV421-A:: IgM Comp-BV421-A:: IgM 51.3 Comp-PE-Cy7-A:: CD93 60.3 Comp-PE-Cy7-A:: CD93 Comp-APC-Cy7-A :: IgD Comp-PE-Alexa 594-A :: CD19 Comp-APC-Cy7-A :: IgD Comp-PE-Alexa 594-A :: CD19 Supplemental Fig.s7 UBXN3B is essential for early B lymphopoiesis in the bone marrow.
Load more

Recommended publications
  • Environments of Haematopoiesis and B-Lymphopoiesis in Foetal Liver K
    Environments of haematopoiesis and B-lymphopoiesis in foetal liver K. Kajikhina1, M. Tsuneto1,2, F. Melchers1 1Max Planck Fellow Research Group ABSTRACT potent myeloid/lymphoid progenitors on “Lymphocyte Development”, In human and murine embryonic de- (MPP), and their immediate progeny, Max Planck Institute for Infection velopment, haematopoiesis and B-lym- common myeloid progenitors (CMP) Biology, Berlin, Germany; phopoiesis show stepwise differentia- and common lymphoid progenitors 2Department of Stem Cell and Developmental Biology, Mie University tion from pluripotent haematopoietic (CLP) soon thereafter (10). The first Graduate School of Medicine, Tsu, Japan. stem cells and multipotent progenitors, T- or B-lymphoid lineage-directed pro- Katja Kajikhina over lineage-restricted lymphoid and genitors appear at E12.5-13.5, for T- Motokazu Tsuneto, PhD myeloid progenitors to B-lineage com- lymphocytes in the developing thymus Fritz Melchers, PhD mitted precursors and finally differenti- (11), for B-lymphocytes in foetal liver Please address correspondence to: ated pro/preB cells. This wave of dif- (12). Time in development, therefore, Fritz Melchers, ferentiation is spatially and temporally separates and orders these different Max Planck Fellow Research Group organised by the surrounding, mostly developmental haematopoietic stages. on “Lymphocyte Development”, non-haematopoietic cell niches. We re- Three-dimensional imaging of progen- Max Planck Institute for Infection Biology, view here recent developments and our itors and precursors indicates that stem Chariteplatz 1, current contributions on the research D-10117 Berlin, Germany. cells are mainly found inside the em- E-mail: [email protected] on blood cell development. bryonic blood vessel, and are attracted Received and accepted on August 28, 2015.
    [Show full text]
  • Cells, Tissues and Organs of the Immune System
    Immune Cells and Organs Bonnie Hylander, Ph.D. Aug 29, 2014 Dept of Immunology [email protected] Immune system Purpose/function? • First line of defense= epithelial integrity= skin, mucosal surfaces • Defense against pathogens – Inside cells= kill the infected cell (Viruses) – Systemic= kill- Bacteria, Fungi, Parasites • Two phases of response – Handle the acute infection, keep it from spreading – Prevent future infections We didn’t know…. • What triggers innate immunity- • What mediates communication between innate and adaptive immunity- Bruce A. Beutler Jules A. Hoffmann Ralph M. Steinman Jules A. Hoffmann Bruce A. Beutler Ralph M. Steinman 1996 (fruit flies) 1998 (mice) 1973 Discovered receptor proteins that can Discovered dendritic recognize bacteria and other microorganisms cells “the conductors of as they enter the body, and activate the first the immune system”. line of defense in the immune system, known DC’s activate T-cells as innate immunity. The Immune System “Although the lymphoid system consists of various separate tissues and organs, it functions as a single entity. This is mainly because its principal cellular constituents, lymphocytes, are intrinsically mobile and continuously recirculate in large number between the blood and the lymph by way of the secondary lymphoid tissues… where antigens and antigen-presenting cells are selectively localized.” -Masayuki, Nat Rev Immuno. May 2004 Not all who wander are lost….. Tolkien Lord of the Rings …..some are searching Overview of the Immune System Immune System • Cells – Innate response- several cell types – Adaptive (specific) response- lymphocytes • Organs – Primary where lymphocytes develop/mature – Secondary where mature lymphocytes and antigen presenting cells interact to initiate a specific immune response • Circulatory system- blood • Lymphatic system- lymph Cells= Leukocytes= white blood cells Plasma- with anticoagulant Granulocytes Serum- after coagulation 1.
    [Show full text]
  • Instant Notes: Immunology, Second Edition
    Immunology Second Edition The INSTANT NOTES series Series Editor: B.D. Hames School of Biochemistry and Molecular Biology, University of Leeds, Leeds, UK Animal Biology 2nd edition Biochemistry 2nd edition Bioinformatics Chemistry for Biologists 2nd edition Developmental Biology Ecology 2nd edition Immunology 2nd edition Genetics 2nd edition Microbiology 2nd edition Molecular Biology 2nd edition Neuroscience Plant Biology Chemistry series Consulting Editor: Howard Stanbury Analytical Chemistry Inorganic Chemistry 2nd edition Medicinal Chemistry Organic Chemistry 2nd edition Physical Chemistry Psychology series Sub-series Editor: Hugh Wagner Dept of Psychology, University of Central Lancashire, Preston, UK Psychology Cognitive Psychology Forthcoming title Physiological Psychology Immunology Second Edition P.M. Lydyard Department of Immunology and Molecular Pathology, Royal Free and University College Medical School, University College London, London, UK A. Whelan Department of Immunology, Trinity College and St James’ Hospital, Dublin, Ireland and M.W. Fanger Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire, USA © Garland Science/BIOS Scientific Publishers Limited, 2004 First published 2000 This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk.” Second edition published 2004 All rights reserved. No part of this book may be reproduced or
    [Show full text]
  • Plasma Cells: Finding New Light at the End of B Cell Development Kathryn L
    © 2001 Nature Publishing Group http://immunol.nature.com REVIEW Plasma cells: finding new light at the end of B cell development Kathryn L. Calame Plasma cells are cellular factories devoted entire- Upon plasma cell differentiation, there is a marked increase in ly to the manufacture and export of a single prod- steady-state amounts of Ig heavy and light chain mRNA and, when 2 uct: soluble immunoglobulin (Ig). As the final required for IgM and IgA secretion, J chain mRNA . Whether the increase in Ig mRNA is due to increased transcription, increased mediators of a humoral response, plasma cells mRNA stability or, as seems likely, both mechanisms, remains con- play a critical role in adaptive immunity.Although troversial2. There is also an increase in secreted versus membrane intense effort has been devoted to studying the forms of heavy chain mRNA, as determined by differential use of poly(A) sites that may involve the availability of one component of regulation and requirements for early B cell the polyadenylation machinery, cleavage-stimulation factor Cst-643. development, little information has been avail- To accommodate translation and secretion of the abundant Ig able on plasma cells. However, more recent mRNAs, plasma cells have an increased cytoplasmic to nuclear ratio work—including studies on genetically altered and prominent amounts of rough endoplasmic reticulum and secreto- ry vacuoles. mice and data from microarray analyses—has Numerous B cell–specific surface proteins are down-regulated begun to identify the regulatory cascades that upon plasma cell differentiation, including major histocompatibility initiate and maintain the plasma cell phenotype. complex (MHC) class II, B220, CD19, CD21 and CD22.
    [Show full text]
  • Impaired B-Lymphopoiesis, Myelopoiesis, and Derailed Cerebellar Neuron Migration in CXCR4- and SDF-1-Deficient Mice
    Proc. Natl. Acad. Sci. USA Vol. 95, pp. 9448–9453, August 1998 Immunology Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice QING MA*, DAN JONES*†,PAUL R. BORGHESANI†‡,ROSALIND A. SEGAL‡,TAKASHI NAGASAWA§, i TADAMITSU KISHIMOTO¶,RODERICK T. BRONSON , AND TIMOTHY A. SPRINGER*,** *The Center for Blood Research and Department of Pathology, Harvard Medical School, Boston, MA 02115; ‡Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115; §Department of Immunology, Research Institute, Osaka Medical Center for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka 590-02, Japan; ¶Department of Medicine III, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565, Japan; and iDepartment of Pathology, Tufts University School of Medicine and Veterinary Medicine, Boston, MA 02111 Contributed by Timothy A. Springer, June 9, 1998 ABSTRACT The chemokine stromal cell-derived factor 1, individuals is associated with the decline of CD41 cells and SDF-1, is an important regulator of leukocyte and hemato- clinical progression to AIDS. poietic precursor migration and pre-B cell proliferation. The SDF-1 and CXCR4 have several unusual features for a receptor for SDF-1, CXCR4, also functions as a coreceptor for chemokine and receptor. First, SDF-1 is extraordinarily con- T-tropic HIV-1 entry. We find that mice deficient for CXCR4 served in evolution, with only one amino acid substitution die perinatally and display profound defects in the hemato- between the human and mouse proteins (10). Based on the poietic and nervous systems. CXCR4-deficient mice have presence of an intervening amino acid between the two severely reduced B-lymphopoiesis, reduced myelopoiesis in N-terminal cysteines, SDF-1 has been grouped with the CXC fetal liver, and a virtual absence of myelopoiesis in bone chemokine subfamily; however, the protein sequence of SDF-1 marrow.
    [Show full text]
  • The Gamma System, Pathology and Therapeutics
    Postgrad. med. J. (February 1969) 45, 116-128. Postgrad Med J: first published as 10.1136/pgmj.45.520.116 on 1 February 1969. Downloaded from The gamma system, pathology and therapeutics RICARDO HORACIO DE LELLIS M.D. Docente auturizado de Pediatriz de la facultad de Medicinz de Buenos Aires, Medico de los Hospitale del Hospital de Pediatria Pedro de Elizalde, Buenos Aires Hypothesis for the integration of childhood immunity Ford & Micklem, 1963; Harris & Ford, 1964). Thus Advances in the immunobiology of the thymus, bone-marrow cells may replace the thymus after immunological competence and immune response radiation induced atrophy of the thymus. These cells have made it necessary to attempt a provisional may acquire 'distinguishing' properties in the scheme to describe the interplay of 'germ and soil'. thymus (Metcalfe, 1964; Auerbach, 1966) and lose Good & Papermaster (1964) have emphasized the the property of repopulating the bone marrow significance of adaptive immunity which is charac- (Dustin & Gregorie, 1931; Ford, 1966). terized by an immunological memory, the second phase of the homograft reaction and the secondary immunological response. Recently the thymus has Lymphopoiesis in the thymus been ascribed a fundamental place in the phylo- In the initial stages of ontogenesis, thymic genetic and ontogenetic development ofthe lymphoid lymphopoiesis appears to be autonomous. InProtected by copyright. system of the higher vertebrates. The inheritance of succeeding stages it may derive from circulating genetic information for the development of this precursors which settle in the thymus and differen- potential is transmitted through the lymphoid tiate (Trinin & Law, 1963; Sainte Marie & Leblond, system of mammals (Fig.
    [Show full text]
  • TP53INP1 Deficiency Maintains Murine B Lymphopoiesis in Aged Bone Marrow Through Redox-Controlled IL-7R/STAT5 Signaling
    TP53INP1 deficiency maintains murine B lymphopoiesis in aged bone marrow through redox-controlled IL-7R/STAT5 signaling Bochra Zidia,b,1, Christelle Vincent-Faberta,1, Laurent Pouyetb,2, Marion Seillierb,2, Amelle Vandeveldea, Prudence N’guessanb,2, Mathilde Poplineaua, Geoffrey Guittardc, Stéphane J. C. Mancinid,3, Estelle Dupreza,3,4, and Alice Carrierb,3,4 aEpigenetic Factors in Normal and Malignant Hematopoiesis, Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, F-13009 Marseille, France; bStress Cell, Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, F-13009 Marseille, France; cImmunity and Cancer, Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, F-13009 Marseille, France; and dLeuko/Stromal Interactions in Normal and Pathological Hematopoiesis, Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, F-13009 Marseille, France Edited by Rafi Ahmed, Emory University, Atlanta, GA, and approved November 20, 2018 (received for review June 9, 2018) Bone marrow (BM) produces all blood and immune cells deriving factors primarily playing a role in B lineage commitment and dif- from hematopoietic stem cells (HSCs). The decrease of immune cell ferentiation (6, 9, 13–15). production during aging is one of the features of immunosenes- Hematopoietic cell production can be drastically increased, cence. The impact of redox dysregulation in BM aging is still poorly particularly in stress situations such as radiation- or chemotherapy- understood. Here we use TP53INP1-deficient (KO) mice endowed induced BM ablation or infection-driven cytopenia; this increase with chronic oxidative stress to assess the influence of aging- allows the BM and the blood to be replenished (16).
    [Show full text]
  • On the Way to Become a Natural Killer Cell
    REVIEW published: 02 August 2019 doi: 10.3389/fimmu.2019.01812 On the Way to Become a Natural Killer Cell Clara Di Vito 1, Joanna Mikulak 1,2 and Domenico Mavilio 1,2* 1 Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy, 2 Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Milan, Italy Natural Killer (NK) cells are innate lymphocytes playing pivotal roles in host defense and immune-surveillance. The homeostatic modulation of germ-line encoded/non-rearranged activating and inhibitory NK cell receptors (NKRs) determines the capability of these innate lymphocytes to either spare “self” cells or to kill viral-infected, tumor-transformed and heterologous cell targets. However, despite being discovered more than 40 years ago, several aspects of NK cell biology remain unknown or are still being debated. In particular, our knowledge of human NK cell ontogenesis and differentiation is still in its infancy as the majority of our experimental evidence on this topic mainly comes from findings obtained in vitro or with animal models in vivo. Although both the generation and the maintenance of human NK cells are sustained by hematopoietic stem cells (HSCs), the precise site(s) of NK cell development are still poorly defined. Indeed, HSCs and hematopoietic precursors are localized in different Edited by: Eric Vivier, anatomical compartments that also change their ontogenic commitments before INSERM U1104 Centre and after birth as well as in aging. Currently, the main site of NK cell generation and d’immunologie de maturation in adulthood is considered the bone marrow, where their interactions with Marseille-Luminy, France stromal cells, cytokines, growth factors, and other soluble molecules support and drive Reviewed by: Stephen K.
    [Show full text]
  • Lymphopoiesis Cells and Suppresses the Earliest Events in Estrogen
    Soluble Frizzled-Related Protein 1 Is Estrogen Inducible in Bone Marrow Stromal Cells and Suppresses the Earliest Events in Lymphopoiesis This information is current as of October 1, 2021. Takafumi Yokota, Kenji Oritani, Karla P. Garrett, Taku Kouro, Makoto Nishida, Isao Takahashi, Michiko Ichii, Yusuke Satoh, Paul W. Kincade and Yuzuru Kanakura J Immunol 2008; 181:6061-6072; ; doi: 10.4049/jimmunol.181.9.6061 Downloaded from http://www.jimmunol.org/content/181/9/6061 References This article cites 67 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/181/9/6061.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Soluble Frizzled-Related Protein 1 Is Estrogen Inducible in Bone Marrow Stromal Cells and Suppresses the Earliest Events in Lymphopoiesis1 Takafumi Yokota,2* Kenji Oritani,* Karla P.
    [Show full text]
  • Age-Related Changes in Lymphocyte Development and Function
    REVIEW Age-related changes in lymphocyte development and function Phyllis Jean Linton & Kenneth Dorshkind The effects of aging on the immune system are widespread and extend from hematopoietic stem cells and lymphoid progenitors in the bone marrow and thymus to mature lymphocytes in secondary lymphoid organs. These changes combine to result in a diminution of immune responsiveness in the elderly. This review aims to provide an overview of age-related changes in lymphocyte development and function and discusses current controversies in the field of aging research. http://www.nature.com/natureimmunology Involution of the thymus and diminished output of T lymphocytes genetic control2, and genes that influence these properties have are arguably the most recognized changes in the immune system been mapped to several quantitative trait loci2–6. These genes with age. However, it is increasingly evident that the effects of aging could encode functions such as DNA repair or responsiveness to on the immune system are widespread, extending from hematopoi- environmental signals2, and age-related changes in expression or etic stem cells and lymphoid progenitors to mature lymphocytes in activity of their products could in turn affect the quality of HSCs. secondary lymphoid organs. Together, the changes in these popula- The results of competitive repopulation studies, in which young tions combine to cause a substantial diminution in immune respon- and old cells from the same strain are mixed and transplanted into siveness in the elderly. the same recipient, are particularly illustrative of this point: HSCs Many of the age-related phenomena that affect the immune system from old mice show a decreased repopulating efficiency compared have been recognized for some time.
    [Show full text]
  • The Bone Marrow As Sanctuary for Plasma Cells and Memory T-Cells: Implications for Adaptive Immunity and Vaccinology
    cells Review The Bone Marrow as Sanctuary for Plasma Cells and Memory T-Cells: Implications for Adaptive Immunity and Vaccinology Stefan A. Slamanig 1,2,† and Martijn A. Nolte 1,2,* 1 Department of Molecular Hematology, Sanquin Research, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands; [email protected] 2 Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands * Correspondence: [email protected] † Current address: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Abstract: The bone marrow (BM) is key to protective immunological memory because it harbors a major fraction of the body’s plasma cells, memory CD4+ and memory CD8+ T-cells. Despite its paramount significance for the human immune system, many aspects of how the BM enables decade-long immunity against pathogens are still poorly understood. In this review, we discuss the relationship between BM survival niches and long-lasting humoral immunity, how intrinsic and extrinsic factors define memory cell longevity and show that the BM is also capable of adopting many responsibilities of a secondary lymphoid organ. Additionally, with more and more data on the differentiation and maintenance of memory T-cells and plasma cells upon vaccination in humans being reported, we discuss what factors determine the establishment of long-lasting immunological memory in the BM and what we can learn for vaccination technologies and antigen design. Finally, using these insights, we touch on how this holistic understanding of the BM is necessary for the development of modern and efficient vaccines against the pandemic SARS-CoV-2. Citation: Slamanig, S.A.; Nolte, M.A.
    [Show full text]
  • Identification of Novel Human NK Cell Progenitor Subsets
    International Journal of Molecular Sciences Article Identification of Novel Human NK Cell Progenitor Subsets Priyanka Sathe 1,2, Swee Heng Milon Pang 1,2, Rebecca Delconte 1,2 ID , Ngaire Elwood 3,4 and Nicholas D. Huntington 1,2,* 1 The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; [email protected] (P.S.); [email protected] (S.H.M.P.); [email protected] (R.D.) 2 Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia 3 Cord Blood Research, Murdoch Children’s Research Institute, Melbourne, VIC 3052, Australia; [email protected] 4 Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia * Correspondence: [email protected]; Tel.: +61-3-9345-2409 Received: 31 October 2017; Accepted: 8 December 2017; Published: 15 December 2017 Abstract: Understanding the pathways and regulation of human haematopoiesis, in particular, lymphopoiesis, is vital to manipulation of these processes for therapeutic purposes. However, although haematopoiesis has been extensively characterised in mice, translation of these findings to human biology remains rudimentary. Here, we describe the isolation of three progenitor subsets from human foetal bone marrow that represent differential stages of commitment to the natural killer (NK) cell lineage based on IL-15 responsiveness. We identify CD7 as a marker of IL-15 responsive progenitors in human bone marrow and find that this expression is maintained throughout commitment and maturation. Within the CD7+ fraction, we focussed on the lineage potential of three subsets based on CD127 and CD117 expression and observed restricted lymphoid and biased NK cell potential amongst subsets.
    [Show full text]