DOCSLIB.ORG

Developmental Control of Innate Lymphoid Cells

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

DEVELOPMENTAL CONTROL OF INNATE LYMPHOID CELLS By Theresa L. Geiger A Dissertation Presented to the Faculty of the Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy New York, NY May 2016 __________________ __________________ Joseph Sun, PhD Date Dissertation Mentor Copyright © by Theresa Lynn Geiger 2016 Dedication To my family, for all of their love and support “A loveless world is a dead world, and always there comes an hour when one is weary of prisons, of one's work, and of devotion to duty, and all one craves for is a loved face, the warmth and wonder of a loving heart.” - Albert Camus, The Plague - iii Abstract Innate lymphoid cells (ILCs) are a recently defined lineage of cells derived from the common lymphoid progenitor (CLP). They are primarily found at barrier surfaces such as the intestine and skin, and have established roles in homeostasis and protection from pathogens at these sites through their production of cytokines. The founding member of the ILC lineage, natural killer (NK) cells, can also rapidly kill infected or transformed cells. Here, we report on two different players in the complex network of transcription factors and cytokines that govern ILC development: the transcription factor Nfil3 and the cytokine TGF- β. We show that the transcription factor Nfil3 is not only required for the development of NK cells, but also all other ILC lineages. Nfil3-deficient mice lack all ILC subsets, including NK cells, and are severely deficient in an early ILC progenitor. Nfil3-deficient mice are also drastically more susceptible to intestinal pathogens such as C. rodentium and C. difficile, likely due to their lack of intestinal ILCs. Suprisingly, Nfil3-/- mice are only slightly more susceptible to chemically induced colitis and are less susceptible to a carcinogen-induced model of colorectal cancer, indicating ILCs may also play a pathogenic role in certain settings. Furthermore, we show that the cytokine TGF-β is dispensable for normal NK cell development. Deletion of TGF-β signaling in NK cells at the NK progenitor (NKP) stage has no observed affect on NK cell development. However, TGF-β insensitive NK cells appear to have a defect in expansion and persistence after viral infection, indicating that TGF-β may play a role in determining effector and memory NK cell fates. These findings have increased iv our understanding of the complex network of signals governing ILC development. In particular, our identification of Nfil3 as a transcription factor necessary for both NK cell and ILC development helps establish the relationship between these two lineages during early lymphoid development. v Acknowledgements First of all, I would like to thank my thesis mentor, Joe Sun. Thank you for being so supportive and excited about science. I have really enjoyed my time in the lab. Thank you also to all of the current and former Sun lab members: Carolyn Zawislak, Matt Firth, Jenny Karo, Sharline Madera, Aimee Beaulieu, Lexus Johnson, Clair Geary, Tim O’Sullivan, Moritz Rapp, Nick Adams, and Orrel Weizman. You have all been great to work with. Special thanks to Aimee, Jenny, and Sharline, for your great advice about life as well as lab. I would also like to thank our collaborators on the Nfil3 project: Alan Hanash, Marcel van den Brink, Maggie O’Connor, Mike Abt, Eric Pamer, Georg Gasteiger, Andrew Dannenberg, and David Montrose. The project would not have been possible without your advice and expertise. Thank you also to Pooja Khanna, a rotation student who worked with me on the TGF-β project. Thank you to my thesis committee, Ming Li, Jedd Wolchok, and Eric Pamer, for your support, advice, and insight. Thank you also to my external examiner, David Artis, and my exam chair, Alexander Rudensky. Thank you to the rest of the Sloan Kettering and Weill Cornell immunology departments, especially the Rudensky and van den Brink labs, for your help and advice. Thank you to Kathy Hsu, Jeanette Boudreau, and the rest of NK club for your insightful questions and suggestions. Thank you to the National Institutes of Health, National Institute of Allergy and Infectious Disease, and the Starr Cancer Consortium for their funding support. I would also like to thank my undergraduate research mentors, Dinesh vi Rao and David Baltimore, for giving me my first opportunity to pursue biology research. Thank you to all of the Gerstner Sloan Kettering Graduate School. It has been a wonderful, enriching experience and I am so glad I chose to attend GSK. Thank you to Ken Marians, GSK dean, for leading this fantastic graduate school program. Thank you to Linda Burnley, associate dean, for all of your support. Thank you to the GSK administrative staff who keep the school running: Ivan Gerena, Katherine Gentile, Iwona Abramek, and Maria Torres. Maria, thank you for being GSK’s go-to problem solver. Iwona, thank you for all of your help with the dissertation and defense process. Thank you also to the other GSK students, especially my classmates. I look forward to watching all of you do great things in the years to come. Thank you so much to my family and friends for your neverending love and support. To my mother, thank you for reminding me that no time spent learning is ever wasted. To my father, thank you for always encouraging me to pursue my dreams. To Christian, thank you for always being there for me. To Hannah, thank you for your advice and support. To my IMSA and Caltech friends, thank you for being so excited and passionate about learning and achieving new things. To my fiancé, Rob, thank you for letting me drag you out of sunny California to live in crazy New York City for five years. Thank you for all of your love, support, and encouragement. Thank you for agreeing to get a dog. To my dog, Steven, thank you for always being happy to see me. To everyone else who has supported me before or during graduate school, thank you. vii Table of Contents List of Figures ...................................................................................................... xii List of Abbreviations ............................................................................................ xv Chapter 1: Introduction .......................................................................................... 1 I. Development of Innate Lymphoid Cells .......................................................... 1 1. ILC Precursors ............................................................................................ 2 2. Differentiation of ILC1 and NK cells ........................................................... 3 3. Differentiation of ILC2 ................................................................................. 5 4. Differentiation of ILC3 and LTi Cells ........................................................... 6 II. Development and Maturation of Natural Killer Cells1 ................................... 12 1. Stages of NK Cell Development and Differentiation1 ............................... 13 2. Transcriptional Control of Early NK Cell Development1 ........................... 15 3. Transcription Factors Governing NK Cell Maturation1 .............................. 18 4. Regulation of Effector NK Cell Responses and Memory Formation1 ....... 20 III. ILCs in Disease and Homeostasis .............................................................. 26 1. NK cells and ILC1 ..................................................................................... 26 2. ILC2 .......................................................................................................... 27 3. ILC3 and LTi Cells .................................................................................... 28 IV. Summary .................................................................................................... 30 Chapter 2: Nfil3 is Crucial for the Development of all Innate Lymphoid Cells ..... 33 I. Introduction ................................................................................................... 33 1. The Transcription Factor Nfil3/E4BP4 ...................................................... 33 2. Nfil3 in the Immune System ..................................................................... 34 viii II. Results ......................................................................................................... 36 1. Intestinal Group 3 ILCs are Severely Reduced in Nfil3-deficient Mice2 .... 36 2. Cell-intrinsic Requirement for Nfil3 in ILC3 Development2 ....................... 37 3. Nfil3 is Essential for Resistance Against Intestinal Pathogens2 ............... 37 4. Development of the ILC Precursor Depends on Nfil32 ............................. 40 5. Nfil3-independent Maintenance of Mature NKp46+ ILC3s2 ...................... 41 6. ILC2 Populations are Severely Diminished in Nfil3-deficient Mice2 .......... 41 7. Nfil3-/- and WT Mice Develop Similar Levels of Colitis After DSS Treatment ..................................................................................................... 43 8. Nfil3-/- Mice are Less Susceptible to AOM/DSS Polyp Formation ............ 44 III. Discussion ................................................................................................... 60 IV. Materials and Methods ............................................................................... 63 1. Mice2 ......................................................................................................... 63 2.
Recommended publications
  • Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model

    Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model

    Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A.
  • NFIL3 Mutations Alter Immune Homeostasis and Sensitise For

    NFIL3 Mutations Alter Immune Homeostasis and Sensitise For

    Ann Rheum Dis: first published as 10.1136/annrheumdis-2018-213764 on 14 December 2018. Downloaded from Basic and translational research EXTENDED REPORT NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology Susan Schlenner,1,2 Emanuela Pasciuto,1,2 Vasiliki Lagou,1,2 Oliver Burton,1,2 Teresa Prezzemolo,1,2 Steffie Junius,1,2 Carlos P Roca,1,2 Cyril Seillet,3,4 Cynthia Louis,3 James Dooley,1,2 Kylie Luong,3,4 Erika Van Nieuwenhove,1,2,5 Ian P Wicks,3,4 Gabrielle Belz,3,4 Stéphanie Humblet-Baron,1,2 Carine Wouters,1,5 Adrian Liston1,2 Handling editor Josef S ABSTRact Key messages Smolen Objectives NFIL3 is a key immunological transcription factor, with knockout mice studies identifying functional ► Additional material is Homozygous NFIL3 mutations identified in roles in multiple immune cell types. Despite the importance ► published online only. To view monozygotic twins with juvenile idiopathic please visit the journal online of NFIL3, little is known about its function in humans. arthritis. (http:// dx. doi. org/ 10. 1136/ Methods Here, we characterised a kindred of two Enhanced susceptibility to arthritis induction in annrheumdis- 2018- 213764). monozygotic twin girls with juvenile idiopathic arthritis at ► Nfil3-knockout mice. 1 the genetic and immunological level, using whole exome Department of Microbiology NFIL3 loss in patients and mice is associated sequencing, single cell sequencing and flow cytometry. ► and Immunology, KUL - with elevated production of IL-1 . University of Leuven, Leuven, Parallel studies were performed in a mouse model. β Knockdown of NFIL3 in healthy macrophages Belgium Results The patients inherited a novel p.M170I in NFIL3 ► 2VIB Center for Brain and drives IL-1β production.
  • Susceptibility of Heterozygous and Nullizygous P53 Knockout Mice to Chemical Carcinogens: Tissue Dependence and Role of P53 Gene Mutations

    Susceptibility of Heterozygous and Nullizygous P53 Knockout Mice to Chemical Carcinogens: Tissue Dependence and Role of P53 Gene Mutations

    J Toxicol Pathol 2005; 18: 121–134 Review Susceptibility of Heterozygous and Nullizygous p53 Knockout Mice to Chemical Carcinogens: Tissue Dependence and Role of p53 Gene Mutations Tetsuya Tsukamoto1, Akihiro Hirata1, and Masae Tatematsu1 1Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1–1 Kanokoden, Chikusa-ku, Nagoya 464–8681, Japan Abstract: Mutations of the p53 tumor suppressor gene constitute one of the most frequent molecular changes in a wide variety of human cancers and mice deficient in p53 have recently attracted attention for their potential to identify chemical genotoxins. In this article, we review the data on the susceptibility of p53 nullizygote (–/–), heterozygote (+/ –), and wild type (+/+) mice to various carcinogens. Induction of esophageal and tongue squamous cell carcinomas (SCCs) by methyl-n-amylnitrosamine was shown to be increased in p53 (+/–) mice, in addition to the high sensitivity shown by p53 (–/–) littermates. N,N-dibutylnitrosamine (DBN) treatment also caused more tumor development in p53 (+/–) than wild-type mice, as with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the urinary bladder. In addition, p53 (+/–) heterozygotes proved more sensitive than wild type littermates to the induction of stromal cell tumors like hemangiomas/hemangiosarcomas by N-bis(2-hydroxypropyl)nitrosamine (BHP) or lymphomas and fibrosarcomas with other carcinogens. Analysis of exons 5–8 of the p53 gene demonstrated mutations in approximately one half of the lesions. With N-methyl-N-nitrosourea, preneoplastic lesions of the stomach, pepsinogen altered pyloric glands (PAPG), and a gastric adenocarcinoma, were found after only 15 weeks in p53 (–/–) mice, although there was no significant difference in the incidence of gastric tumors between p53 (+/+) and (+/–) mice in the longer-term.
  • Transcriptional Control of Tissue-Resident Memory T Cell Generation

    Transcriptional Control of Tissue-Resident Memory T Cell Generation

    Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2019 © 2019 Filip Cvetkovski All rights reserved ABSTRACT Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Tissue-resident memory T cells (TRM) are a non-circulating subset of memory that are maintained at sites of pathogen entry and mediate optimal protection against reinfection. Lung TRM can be generated in response to respiratory infection or vaccination, however, the molecular pathways involved in CD4+TRM establishment have not been defined. Here, we performed transcriptional profiling of influenza-specific lung CD4+TRM following influenza infection to identify pathways implicated in CD4+TRM generation and homeostasis. Lung CD4+TRM displayed a unique transcriptional profile distinct from spleen memory, including up-regulation of a gene network induced by the transcription factor IRF4, a known regulator of effector T cell differentiation. In addition, the gene expression profile of lung CD4+TRM was enriched in gene sets previously described in tissue-resident regulatory T cells. Up-regulation of immunomodulatory molecules such as CTLA-4, PD-1, and ICOS, suggested a potential regulatory role for CD4+TRM in tissues. Using loss-of-function genetic experiments in mice, we demonstrate that IRF4 is required for the generation of lung-localized pathogen-specific effector CD4+T cells during acute influenza infection. Influenza-specific IRF4−/− T cells failed to fully express CD44, and maintained high levels of CD62L compared to wild type, suggesting a defect in complete differentiation into lung-tropic effector T cells.
  • T Cell Factor 1 Is Required for Group 2 Innate Lymphoid Cell Generation

    T Cell Factor 1 Is Required for Group 2 Innate Lymphoid Cell Generation

    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Immunity Article T Cell Factor 1 Is Required for Group 2 Innate Lymphoid Cell Generation Qi Yang,1 Laurel A. Monticelli,2 Steven A. Saenz,2 Anthony Wei-Shine Chi,1 Gregory F. Sonnenberg,2 Jiangbo Tang,3 Maria Elena De Obaldia,1 Will Bailis,1 Jerrod L. Bryson,1 Kristin Toscano,1 Jian Huang,4 Angela Haczku,4 Warren S. Pear,1 David Artis,2 and Avinash Bhandoola1,* 1Department of Pathology and Laboratory Medicine 2Department of Microbiology 3Department of Cancer Biology 4Department of Medicine Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.immuni.2012.12.003 SUMMARY 2012b; Hoyler et al., 2012; Moro et al., 2010; Wong et al., 2012). However, other transcription factors implicated in the Group 2 innate lymphoid cells (ILC2) are innate generation and function of ILC2 remain to be identified. lymphocytes that confer protective type 2 immunity ILC2 share many similarities with T cells. ILC2 derive from during helminth infection and are also involved in lymphoid progenitors and phenotypically resemble double- allergic airway inflammation. Here we report that negative 3 (DN3) cells that are committed to the T cell lineage ILC2 development required T cell factor 1 (TCF-1, (Moro et al., 2010; Neill et al., 2010; Price et al., 2010; Wong the product of the Tcf7 gene), a transcription factor et al., 2012; Yang et al., 2011).
  • ILC2 Activation by Protozoan Commensal Microbes

    ILC2 Activation by Protozoan Commensal Microbes

    International Journal of Molecular Sciences Review ILC2 Activation by Protozoan Commensal Microbes Kyle Burrows 1 , Louis Ngai 1 , Flora Wong 1,2, David Won 1 and Arthur Mortha 1,* 1 University of Toronto, Department of Immunology, Toronto, ON M5S 1A8, Canada; [email protected] (K.B.) [email protected] (L.N.); fl[email protected] (F.W.); [email protected] (D.W.) 2 Ranomics, Inc. Toronto, ON M5G 1X5, Canada * Correspondence: [email protected] Received: 3 September 2019; Accepted: 27 September 2019; Published: 30 September 2019 Abstract: Group 2 innate lymphoid cells (ILC2s) are a member of the ILC family and are involved in protective and pathogenic type 2 responses. Recent research has highlighted their involvement in modulating tissue and immune homeostasis during health and disease and has uncovered critical signaling circuits. While interactions of ILC2s with the bacterial microbiome are rather sparse, other microbial members of our microbiome, including helminths and protozoans, reveal new and exciting mechanisms of tissue regulation by ILC2s. Here we summarize the current field on ILC2 activation by the tissue and immune environment and highlight particularly new intriguing pathways of ILC2 regulation by protozoan commensals in the intestinal tract. Keywords: ILC2; protozoa; Trichomonas; Tritrichomonas musculis; mucosal immunity; taste receptors; succinate; intestinal immunity; type 2 immunity; commensals 1. The ILC Lineage 1.1. The Family of Innate Lymphoid Cells Research over the last decade has redirected focus away from classical immune cell interactions within lymphoid tissues towards immunity within non-lymphoid tissues. Within these tissues, immune interactions involve local adaptation and rapid responses by tissue-resident immune cells.
  • Innate Lymphocytes—Lineage, Localization and Timing of Differentiation

    Innate Lymphocytes—Lineage, Localization and Timing of Differentiation

    Cellular & Molecular Immunology www.nature.com/cmi REVIEW ARTICLE Innate lymphocytes—lineage, localization and timing of differentiation Emily R. Kansler1,2 and Ming O. Li1 Innate lymphocytes are a diverse population of cells that carry out specialized functions in steady-state homeostasis and during immune challenge. While circulating cytotoxic natural killer (NK) cells have been studied for decades, tissue-resident innate lymphoid cells (ILCs) have only been characterized and studied over the past few years. As ILCs have been largely viewed in the context of helper T-cell biology, models of ILC lineage and function have been founded within this perspective. Notably, tissue- resident innate lymphocytes with cytotoxic potential have been described in an array of tissues, yet whether they are derived from the NK or ILC lineage is only beginning to be elucidated. In this review, we aim to shed light on the identities of innate lymphocytes through the lenses of cell lineage, localization, and timing of differentiation. Cellular & Molecular Immunology (2019) 16:627–633; https://doi.org/10.1038/s41423-019-0211-7 INTRODUCTION memory T cells have been described.3 Central memory T (Tcm) Lymphocytes are a fundamental component of the host immune cells are derived from CX3CR1− effector T cells and primarily response to challenge. Different classes of the lymphocyte circulate between the blood and secondary lymphoid organs. response are best defined by the type of effector programs Resident memory T (Trm) cells, although also derived from carried out by CD8+ or CD4+ T cells. CD8+ T cells are cytotoxic CX3CR1− effector T cells, enter peripheral tissues where they are lymphocytes that mediate a type 1 immune response to maintained locally by self-renewal and do not recirculate.
  • The Chemokine System in Innate Immunity

    The Chemokine System in Innate Immunity

    Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press The Chemokine System in Innate Immunity Caroline L. Sokol and Andrew D. Luster Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 Correspondence: [email protected] Chemokines are chemotactic cytokines that control the migration and positioning of immune cells in tissues and are critical for the function of the innate immune system. Chemokines control the release of innate immune cells from the bone marrow during homeostasis as well as in response to infection and inflammation. Theyalso recruit innate immune effectors out of the circulation and into the tissue where, in collaboration with other chemoattractants, they guide these cells to the very sites of tissue injury. Chemokine function is also critical for the positioning of innate immune sentinels in peripheral tissue and then, following innate immune activation, guiding these activated cells to the draining lymph node to initiate and imprint an adaptive immune response. In this review, we will highlight recent advances in understanding how chemokine function regulates the movement and positioning of innate immune cells at homeostasis and in response to acute inflammation, and then we will review how chemokine-mediated innate immune cell trafficking plays an essential role in linking the innate and adaptive immune responses. hemokines are chemotactic cytokines that with emphasis placed on its role in the innate Ccontrol cell migration and cell positioning immune system. throughout development, homeostasis, and in- flammation. The immune system, which is de- pendent on the coordinated migration of cells, CHEMOKINES AND CHEMOKINE RECEPTORS is particularly dependent on chemokines for its function.
  • NK Cell Development in Times of Innate Lymphoid Cell Diversity

    NK Cell Development in Times of Innate Lymphoid Cell Diversity

    REVIEW published: 08 July 2020 doi: 10.3389/fimmu.2020.00813 NK Cell Development in Times of Innate Lymphoid Cell Diversity Vladislava Stokic-Trtica 1,2, Andreas Diefenbach 1,3,4* and Christoph S. N. Klose 1* 1 Department of Microbiology, Infectious Diseases and Immunology, Charité–Universitätsmedizin Berlin, Berlin, Germany, 2 Max-Planck Institute for Infection Biology, Berlin, Germany, 3 Berlin Institute of Health (BIH), Berlin, Germany, 4 Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, Berlin, Germany After being described in the 1970s as cytotoxic cells that do not require MHC-dependent pre-activation, natural killer (NK) cells remained the sole member of innate lymphocytes for decades until lymphoid tissue-inducer cells in the 1990s and helper-like innate lymphoid lineages from 2008 onward completed the picture of innate lymphoid cell (ILC) diversity. Since some of the ILC members, such as ILC1s and CCR6− ILC3s, share specific markers previously used to identify NK cells, these findings provoked the question of how to delineate the development of NK cell and helper-like ILCs and how to properly identify and genetically interfere with NK cells. The description of eomesodermin Edited by: (EOMES) as a lineage-specifying transcription factor of NK cells provided a candidate Ewa Sitnicka, Lund University, Sweden that may serve as a selective marker for the genetic targeting and identification of Reviewed by: NK cells. Unlike helper-like ILCs, NK cell activation is, to a large degree, regulated Gabrielle Belz, by the engagement of activating and inhibitory surface receptors. NK cell research Walter and Eliza Hall Institute of has revealed some elegant mechanisms of immunosurveillance, coined “missing-self” Medical Research, Australia Barbara L.
  • Gene Expression Patterns Define Novel Roles for E47 in Cell Cycle Progression, Cytokine-Mediated Signaling, and T Lineage Development

    Gene Expression Patterns Define Novel Roles for E47 in Cell Cycle Progression, Cytokine-Mediated Signaling, and T Lineage Development

    Gene expression patterns define novel roles for E47 in cell cycle progression, cytokine-mediated signaling, and T lineage development Ruth Schwartz*†, Isaac Engel*†‡, Mohammad Fallahi-Sichani§, Howard T. Petrie§, and Cornelis Murre*¶ *Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093-0377; and §Scripps͞Florida Research Institute, 5353 Parkside Drive, RF-1, Jupiter, FL 33458 Communicated by Michael S. Levine, University of California, Berkeley, CA, May 5, 2006 (received for review April 7, 2006) In maturing T lineage cells, the helix–loop–helix protein E47 has analyze the global patterns of gene expression in E2A-deficient been shown to enforce a critical proliferation and developmental lymphomas in the absence and presence of E47. Cluster analysis checkpoint commonly referred to as ␤ selection. To examine how identified groups of genes that were regulated by E47 and shared E47 regulates cellular expansion and developmental progression, biochemical or physiological properties. These included genes we have used an E2A-deficient lymphoma cell line and DNA involved in cell survival, cell cycle progression, stress response, lipid microarray analysis to identify immediate E47 target genes. Hier- metabolism, ␣␤, and natural killer T (NKT) cell function. Based on archical cluster analysis of gene expression patterns revealed that these observations, we suggest that E47 functions in molecular E47 coordinately regulates the expression of genes involved in cell pathways to coordinate cell survival, cell growth, and developmen- survival, cell cycle progression, lipid metabolism, stress response, tal maturation. We identified cyclin-dependent kinase 6 (Cdk6) as and lymphoid maturation. These include Plc␥2, Cdk6, CD25, Tox, an E47 target gene, providing a potential mechanism underlying a Gadd45a, Gadd45b, Gfi1, Gfi1b, Socs1, Socs3, Id2, Eto2, and Xbp1.
  • Innate Lymphoid Cells (Ilcs): Cytokine Hubs Regulating Immunity and Tissue Homeostasis

    Innate Lymphoid Cells (Ilcs): Cytokine Hubs Regulating Immunity and Tissue Homeostasis

    Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Innate Lymphoid Cells (ILCs): Cytokine Hubs Regulating Immunity and Tissue Homeostasis Maho Nagasawa, Hergen Spits, and Xavier Romero Ros Department of Experimental Immunology, Academic Medical Center at the University of Amsterdam, 1105 BA Amsterdam, Netherlands Correspondence: [email protected] Innate lymphoid cells (ILCs) have emerged as an expanding family of effector cells particu- larly enriched in the mucosal barriers. ILCs are promptly activated by stress signals and multiple epithelial- and myeloid-cell-derived cytokines. In response, ILCs rapidly secrete effector cytokines, which allow them to survey and maintain the mucosal integrity. Uncontrolled action of ILCs might contribute to tissue damage, chronic inflammation, met- abolic diseases, autoimmunity, and cancer. Here we discuss the recent advances in our understanding of the cytokine network that modulate ILC immune responses: stimulating cytokines, signature cytokines secreted by ILC subsets, autocrine cytokines, and cytokines that induce cell plasticity. nnate lymphoid cells (ILCs) are innate lym- Klose et al. 2014; Gasteiger et al. 2015). ILCs Iphocytes that play important roles in immune cross talk with the resident tissue by sensing defense against microbes, regulation of adaptive the cytokines present in their microenviron- immunity, tissue remodeling, and repair and ments and subsequently secreting a plethora homeostasis of hematopoietic and nonhemato- of cytokines that regulate innate immunity poietic cell types. ILCs are present in all tissues, and homeostasis of hematopoietic and nonhe- but they are particularly enriched in mucosal matopoietic cells in the tissues (Artis and Spits surfaces. Unlike adaptive lymphocytes, ILCs 2015).
  • Supplementary Material Contents

    Supplementary Material Contents

    Supplementary Material Contents Immune modulating proteins identified from exosomal samples.....................................................................2 Figure S1: Overlap between exosomal and soluble proteomes.................................................................................... 4 Bacterial strains:..............................................................................................................................................4 Figure S2: Variability between subjects of effects of exosomes on BL21-lux growth.................................................... 5 Figure S3: Early effects of exosomes on growth of BL21 E. coli .................................................................................... 5 Figure S4: Exosomal Lysis............................................................................................................................................ 6 Figure S5: Effect of pH on exosomal action.................................................................................................................. 7 Figure S6: Effect of exosomes on growth of UPEC (pH = 6.5) suspended in exosome-depleted urine supernatant ....... 8 Effective exosomal concentration....................................................................................................................8 Figure S7: Sample constitution for luminometry experiments..................................................................................... 8 Figure S8: Determining effective concentration .........................................................................................................