DOCSLIB.ORG

Thymic Deletion and Regulatory T Cells Prevent Antimyeloperoxidase GN

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Thymic Deletion and Regulatory T Cells Prevent Antimyeloperoxidase GN BASIC RESEARCH www.jasn.org Thymic Deletion and Regulatory T Cells Prevent Antimyeloperoxidase GN † ‡ Diana S.Y. Tan,* Poh Y. Gan,* Kim M. O’Sullivan,* Maree V. Hammett, Shaun A. Summers,* † ‡ Joshua D. Ooi,* Brita A. Lundgren,§ Richard L. Boyd, Hamish S. Scott,§ A. Richard Kitching,* † ‡ Ann P. Chidgey, and Stephen R. Holdsworth* *Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia; †Immune Regeneration Laboratory, Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Australia; ‡Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia; and §Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia ABSTRACT Loss of tolerance to neutrophil myeloperoxidase (MPO) underlies the development of ANCA-associated vasculitis and GN, but the mechanisms underlying this loss of tolerance are poorly understood. Here, we assessed the role of the thymus in deletion of autoreactive anti-MPO T cells and the importance of pe- ripheral regulatory T cells in maintaining tolerance to MPO and protecting from GN. Thymic expression of MPO mRNA predominantly localized to medullary thymic epithelial cells. To assess the role of MPO in forming the T cell repertoire and the role of the autoimmune regulator Aire in thymic MPO expression, we 2/2 2/2 compared the effects of immunizing Mpo mice, Aire mice, and control littermates with MPO. 2/2 2/2 Immunized Mpo and Aire mice developed significantly more proinflammatory cytokine-producing anti-MPO T cells and higher ANCA titers than control mice. When we triggered GN with a subnephrito- 2/2 genic dose of anti-glomerular basement membrane antibody, Aire mice had more severe renal disease +/+ than Aire mice, consistent with a role for Aire-dependent central deletion in establishing tolerance to MPO. Furthermore, depleting peripheral regulatory T cells in wild-type mice also led to more anti-MPO T cells, higher ANCA titers, and more severe GN after immunization with MPO. Taken together, these results suggest that Aire-dependent central deletion and regulatory T cell–mediated peripheral tolerance both play major roles in establishing and maintaining tolerance to MPO, thereby protecting against the development of anti-MPO GN. J Am Soc Nephrol 24: 573–585, 2013. doi: 10.1681/ASN.2012090898 Systemic autoimmunity to myeloperoxidase system to discriminate between self and non-self (MPO) is directly involved in causing the glomeru- antigens. Central tolerance involves thymic deletion lar and vascular inflammation of ANCA-associated of thymocytes with high-affinity interactions be- pauci-immune necrotizing autoimmune anti-MPO tween the T cell receptor and self-peptide MHC GN (AIMPOGN).1–3 ANCA induces neutrophil ac- complexes, preventing many potentially autoreac- tivation and endothelial cell adhesion, with the re- tive T cells from entering the periphery.9 The role of lease of neutrophil extracellular traps containing 4, MPO and proteases triggering endothelial injury. Received September 10, 2012. Accepted December 21, 2012. 5 Experimental studies demonstrate that autoim- Published online ahead of print. Publication date available at mune anti-MPO CD4+ T cells respond to glomer- www.jasn.org. ular MPO deposited by degranulating neutrophils, Correspondence: Prof. Stephen R. Holdsworth, Centre for In- directing injurious delayed type hypersensitivity flammatory Diseases, Monash University Department of Medi- (DTH)–mediated injury.6–8 cine, Monash Medical Centre, 246 Clayton Road, Clayton, VIC Immunologic tolerance is maintained by central 3168, Australia. Email: [email protected] and peripheral mechanisms, allowing the immune Copyright © 2013 by the American Society of Nephrology J Am Soc Nephrol 24: 573–585, 2013 ISSN : 1046-6673/2404-573 573 BASIC RESEARCH www.jasn.org central tolerance in the maintenance of tolerance to the po- low-expressing mTECs (mTEC-lo) (Figure 1B). Expression tential kidney autoantigen, MPO, is largely unknown. The in mTEC-hi is consistent with the known critical involvement autoimmune regulator (Aire) transcription factor is impor- of these cells in the development of the T cell repertoire.31 tant for the induction and regulation of tolerance.10–12 Aire Given that Aire is expressed only on the CD452 nonhemato- is primarily found in lymphoid organs, particularly in the poietic population, and predominantly by the mature mTECs thymus where it is predominantly found in the nuclei of (mTECs-hi) (Figure 1, C and D), we determined whether 2 2 mature, highly MHC II–expressing13–15 medullary thymic MPO expression would be altered in Aire / mice. We found epithelial cells (mTECs).16,17 Aire promotes the promiscu- that MPO expression was almost absent from the mTEC-hi 2 2 ous expression of tissue-restricted antigens (TRAs) in and mTEC-lo cells in Aire / mice (Figure 1B), suggesting a mTECs.13,16–18 However, the mechanisms by which Aire strong association with Aire-dependent peripheral antigen ex- controls the presentation of TRA expression in mTECs and pression. its effect on tolerance and autoimmunity remain to be fully defined. MPO Protein Expression Confined to Neutrophils and Despite central tolerance, some autoreactive cells escape Macrophages the selection process, entering the periphery where they may The presence of MPO protein was determined by immunohis- cause autoimmunity if activated.19,20 Naturally arising CD4 tology staining. We examined the thymi of 5-week-old Mpo+/+, 2 2 2 2 +CD25+Foxp3+ regulatory T cells (Tregs), mainly produced Mpo / , and Aire / mice (Figure 2, A–C, respectively). MPO 2 2 by the thymus by high-affinity interactions with thymic ep- protein is present in Mpo+/+ and Aire / mice, but as expected, 2 2 ithelial cells,21 are a distinct T cell population that plays a absent from Mpo / thymi (Figure 2, A–C). The MPO distri- pivotal role in the maintenance of self-tolerance. Several bution was along the corticomedullary junction. Colocaliza- studies demonstrate the importance of Tregs in the preven- tion studies demonstrated MPO localization to neutrophils tion of organ-specific autoimmunity by potently sup- (Figure 2, D–F) and macrophages (Figure 2, G–I) in the thymic pressing autoreactive T cells in a contact-dependent and compartment of all five thymus samples. Confocal immuno- cytokine-independent manner.22–26 Depletion of Tregs leads fluorescence microscopy revealed that all neutrophils and some to the spontaneous development of some autoimmune dis- macrophages are MPO positive. It was also evident that most of eases.27–29 the MPO positive cells are neutrophils. To assess the role of central and peripheral tolerance in regulating the development of autoimmunity to MPO, we Thymic Aire-Dependent MPO Expression Deletes used a validated model of MPO-induced autoimmunity.6,7,30 Potentially Autoreactive Anti-MPO T Cells and Protects Establishment of anti-MPO autoimmunity directs the devel- against AIMPOGN opment of focal necrotizing GN similar to that seen in human We assessed MPO-specific cell-mediated immune responses ANCA-associated GN. Our studies demonstrate the impor- with regard to the Th1 and Th17 subset differentiations in tance of both central and peripheral mechanisms in maintain- lymph node cells (LNs) draining the sites of MPO immuni- ing tolerance to MPO. Aire promotes thymic MPO expression zation and serum levels of MPO-ANCAtiters in groups of wild- 2 2 2 2 2 2 and enhances central deletion of autoreactive anti-MPO T type (WT), Mpo / ,andAire / mice. In both Mpo / and 2 2 cells, whereas peripheral Tregs suppress potentially autoreac- Aire / mice, the frequencies of anti-MPO autoreactive CD4+ tive MPO-specific CD4+ T cells. Both mechanisms limit anti- T cells by enzyme-linked immunosorbent spot (ELISPOT) MPO GN. assay and the titers of circulating MPO-ANCA were increased compared with Mpo+/+ (Figure3,A,B,F–H) and Aire+/+ lit- termate WT controls (Figure 3, C and I). The dermal DTH 2 2 RESULTS response to MPO was also increased in Aire / mice (Figure 3D). A control protein, ovalbumin (OVA) in Freund’scom- MPO mRNA Is Predominantly Expressed by MHC II– plete adjuvant (FCA), did not induce anti-MPO autoimmu- Expressing Medullary Thymic Epithelial Cells in an Aire- nity in Mpo+/+ mice. Circulating anti-MPO lgG, lgG1, and Dependent Manner lgG2c levels (Figure 3, E–G) were detected in normal Mpo+/+ After enzymatic digestion of thymic tissue and flow cytometric mice after MPO immunization (not in OVA-immunized mice), 2 2 2 2 sorting of thymic stromal cell (TSC) subsets, transcripts for but were significantly higher in Mpo / and Aire / mice (Fig- 2 2 2 2 MPO were detected in the Mpo+/+ mice, but not in Mpo / ure 3H). There was no difference between Mpo+/+ and Mpo / mice, which served as a negative control. Within the mouse mice in the frequency of Foxp3+ expression of the CD4+ T cells thymus, MPO mRNA is highly expressed in the CD452 TSC isolated from LNs draining the sites of injection (Figure 3, I and subpopulation, but was only minimally detected in the CD45+ J).TheabsenceofthymicMPOandAireaffectedtheinducible thymic hematopoietic subpopulation (Figure 1A). Of the repertoire of autoreactive anti-MPO CD4+ T cells and the levels CD452 population, the major cell subpopulation expressing of autoantibody in a manner consistent with a role for thymic MPO mRNA was the mTECs. MPO was expressed in both the expression of MPO in deleting potentially autoreactive anti-MPO MHC II high-expressing mTECs (mTECs-hi) and MHC II CD4+ T cells. 574 Journal of the American Society of Nephrology J Am Soc Nephrol 24: 573–585, 2013 www.jasn.org BASIC RESEARCH Figure 1. Expression of MPO and Aire mRNA by thymic cell populations, including hematopoietic TECs (CD45+), nonhematopoietic TECs (CD452), medullary TECs (mTECs), cortical TECs (cTECs), and non-TECs (nTECs) with either high (hi) or low (lo) coexpression of MHC II, and dendritic cells (DCs). (A) MPO is predominantly expressed on nonhematopoietic populations in the Mpo+/+ thymus. (B) 2 2 MPO is predominantly seen in MHC II coexpressing mTECs in the WT mice compared with the Aire / mice.
Load more

Recommended publications
  • FOXN1 Deficiency: from the Discovery to Novel Therapeutic Approaches
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Archivio della ricerca - Università degli studi di Napoli Federico II J Clin Immunol DOI 10.1007/s10875-017-0445-z CME REVIEW FOXN1 Deficiency: from the Discovery to Novel Therapeutic Approaches Vera Gallo1 & Emilia Cirillo1 & Giuliana Giardino1 & Claudio Pignata1 Received: 29 June 2017 /Accepted: 11 September 2017 # Springer Science+Business Media, LLC 2017 Abstract Since the discovery of FOXN1 deficiency, the hu- cellular and humoral immunity. To date, more than 20 genetic man counterpart of the nude mouse, a growing body of evi- alterations have been identified as responsible for the disease dence investigating the role of FOXN1 in thymus and skin, [1]. Among these, the FOXN1 gene mutation, causative of the has been published. FOXN1 has emerged as fundamental for nude SCID phenotype, is the unique condition in which the thymus development, function, and homeostasis, representing immunological defect is related to an alteration of the thymic the master regulator of thymic epithelial and T cell develop- epithelial stroma and not to an intrinsic defect of the hemato- ment. In the skin, it also plays a pivotal role in keratinocytes poietic cell. The nude SCID phenotype has been identified in and hair follicle cell differentiation, although the underlying human for the first time in 1996 in two female patients who molecular mechanisms still remain to be fully elucidated. The presented with thymus aplasia and ectodermal abnormalities nude severe combined immunodeficiency phenotype is in- [2], approximately 30 years later than the initial description of deed characterized by the clinical hallmarks of athymia with the murine counterpart.
    [Show full text]
  • Thymic Epithelial Progenitor Cells and Thymus Regeneration: an Update
    npg Progenitor cells and thymus regeneration 50 Cell Research (2007) 17: 50-55 npg © 2007 IBCB, SIBS, CAS All rights reserved 1001-0602/07 $ 30.00 REVIEW www.nature.com/cr Thymic epithelial progenitor cells and thymus regeneration: an update Lianjun Zhang1,2, Liguang Sun1,3, Yong Zhao1 1Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zo- ology, 2Graduate University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100080, China; 3School of Public Health, Jilin University, Changchun 130021, China The thymus provides the essential microenvironment for T-cell development and maturation. Thymic epithelial cells (TECs), which are composed of thymic cortical epithelial cells (cTECs) and thymic medullary epithelial cells (mTECs), have been well documented to be critical for these tightly regulated processes. It has long been controversial whether the common progenitor cells of TECs could give rise to both cTECs and mTECs. Great progress has been made to charac- terize the common TEC progenitor cells in recent years. We herein discuss the sole origin paradigm with regard to TEC differentiation as well as these progenitor cells in thymus regeneration. Cell Research (2007) 17:50-55. doi:10.1038/sj.cr.7310114; published online 5 December 2006 Keywords: thymic epithelial progenitor cells, thymus organogenesis, thymus regeneration Introduction ling events still remain poorly understood [7-9]. Only the thymocytes recognizing major histocompatibility complex In general, stem cells are characterized by two funda- (MHC)-self peptide complexes in an appropriate avidity mental properties of self-renewal potential and further can survive the stringent positive and negative selections differentiation into several specialized cell types.
    [Show full text]
  • Medullary Thymic Epithelial NF–Kb-Inducing Kinase (NIK)/Ikkα Pathway Shapes Autoimmunity and Liver and Lung Homeostasis in Mice
    Medullary thymic epithelial NF–kB-inducing kinase (NIK)/IKKα pathway shapes autoimmunity and liver and lung homeostasis in mice Hong Shena, Yewei Jia, Yi Xionga, Hana Kima, Xiao Zhonga, Michelle G. Jina, Yatrik M. Shaha, M. Bishr Omarya,1, Yong Liub, Ling Qia, and Liangyou Ruia,c,2 aDepartment of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109; bCollege of Life Sciences, The Institute for Advanced Studies, Wuhan University, 430072 Wuhan, China; and cDepartment of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 Edited by Sankar Ghosh, Columbia University Medical Center, New York, NY, and accepted by Editorial Board Member Ruslan Medzhitov August 5, 2019 (received for review January 22, 2019) Aberrant T cell development is a pivotal risk factor for autoim- humans. However, NIK target cells remain elusive. We postu- mune disease; however, the underlying molecular mechanism of lated that mTEC NIK/IKKα pathways might mediate thymo- T cell overactivation is poorly understood. Here, we identified NF– cyte–mTEC crosstalk, shaping mTEC growth and differentiation. κB-inducing kinase (NIK) and IkB kinase α (IKKα) in thymic epithe- To test this hypothesis, we generated and characterized TEC- Δ Δ lial cells (TECs) as essential regulators of T cell development. specific NIK (NIK TEC) and IKKα (IKKα TEC) knockout mice. Mouse TEC-specific ablation of either NIK or IKKα resulted in se- Using these mice, we firmly established a pivotal role of the vere T cell-mediated inflammation, injury, and fibrosis in the liver mTEC-intrinsic NIK/IKKα pathway in mTEC development and and lung, leading to premature death within 18 d of age.
    [Show full text]
  • How Thymic Antigen Presenting Cells Sample the Body's Self-Antigens
    Available online at www.sciencedirect.com How thymic antigen presenting cells sample the body’s self-antigens Jens Derbinski and Bruno Kyewski Our perception of the scope self-antigen availability for recognition on the various thymic antigen presenting tolerance induction in the thymus has profoundly changed over cells (APCs) subsets foremost in the medulla. Hence the recent years following new insights into the cellular and the scope of central tolerance is dictated by the available molecular complexity of intrathymic antigen presentation. The repertoire of self-peptides displayed by thymic APCs, diversity of self-peptide display is on the one hand afforded by which for a long time have been thought to exclude the remarkable heterogeneity of thymic antigen presenting peripheral tissue-specific antigens. cells (APCs) and on the other hand by the endowment of these cells with unconventional molecular pathways. Recent studies Here we will address recent developments adding to our show that each APC subset appears to carry its specific current understanding of the generation of the proteome antigen cargo as a result of cell-type specific features: firstly, and MHC/peptidome by thymic stromal cells, a process transcriptional control (i.e. promiscuous gene expression in which has turned out to be much more intricate than medullary thymic epithelial cells); secondly, antigen processing previously assumed. We will point out that despite the (i.e. proteasome composition and protease sets); thirdly, large number of self-peptides covering each peripheral intracellular antigen sampling (i.e. autophagy in thymic tissue, several recent experimental studies document an epithelial cells) and fourthly, extracellular antigen sampling (i.e.
    [Show full text]
  • ©Ferrata Storti Foundation
    Acute Lymphoblastic Leukemia research paper Thymic epithelial cells promote survival of human T-cell acute lymphoblastic leukemia blasts: the role of interleukin-7 MARIA T. SCUPOLI, FABRIZIO VINANTE, MAURO KRAMPERA, CARLO VINCENZI, GIANPAOLO NADALI, FRANCESCA ZAMPIERI, MARY A. RITTER, EFREM EREN, FRANCESCO SANTINI, GIOVANNI PIZZOLO Background and Objectives. T-cell lymphoblastic -cell acute lymphoblastic leukemia (T-ALL) is a leukemia (T-ALL) cells originate within the thymus from malignant disease resulting from the clonal prolif- the clonal expansion of T cell precursors. Among thymic Teration of T lymphoid precursors. It accounts for stromal elements, epithelial cells (TEC) are known to exert about 15% of all ALL cases in children and 20-25% in a dominant inductive role in survival and maturation of adults.1,2 T-ALL is thought to originate inside the thy- normal, immature T-cells. In this study we explored the mus and leukemic cells express phenotypic features cor- possible effect of TEC on T-ALL cell survival and analyzed responding to distinct maturational stages of thymo- the role of interleukin-7 (IL-7) within the microenviron- cyte development: early (stage I), intermediate (stage II), ment generated by T-ALL-TEC interactions. or late (stage III).2,3 Design and Methods. T-ALL blasts derived from 10 The thymus is the main site where bone marrow adult patients were cultured with TEC obtained from (BM)-derived stem cells differentiate into mature, human normal thymuses. The level of blast apoptosis was immunocompetent T lymphocytes.4,5 The internal stro- measured by annexin V-propidium iodide co-staining and mal framework of the thymus is composed of epithelial flow cytometry.
    [Show full text]
  • Thymic Epithelial Cells Ontogeny and Regulation of IL-7-Expressing
    Ontogeny and Regulation of IL-7-Expressing Thymic Epithelial Cells Monica Zamisch, Billie Moore-Scott, Dong-ming Su, Philip J. Lucas, Nancy Manley and Ellen R. Richie This information is current as of September 30, 2021. J Immunol 2005; 174:60-67; ; doi: 10.4049/jimmunol.174.1.60 http://www.jimmunol.org/content/174/1/60 Downloaded from References This article cites 67 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/174/1/60.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 30, 2021 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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Ontogeny and Regulation of IL-7-Expressing Thymic Epithelial Cells1 Monica Zamisch,* Billie Moore-Scott,† Dong-ming Su,† Philip J. Lucas,‡ Nancy Manley,† and Ellen R. Richie2* Epithelial cells in the thymus produce IL-7, an essential cytokine that promotes the survival, differentiation, and proliferation of thymocytes.
    [Show full text]
  • Immunodeficiency Mouse Thymus Organization in Health and Three-Dimensional Visualization Of
    Three-Dimensional Visualization of the Mouse Thymus Organization in Health and Immunodeficiency This information is current as Magali Irla, Jeanne Guenot, Gregg Sealy, Walter Reith, Beat of October 1, 2021. A. Imhof and Arnauld Sergé J Immunol published online 17 December 2012 http://www.jimmunol.org/content/early/2012/12/16/jimmun ol.1200119 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2012/12/18/jimmunol.120011 Material 9.DC1 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 • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 1, 2021 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 © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published December 17, 2012, doi:10.4049/jimmunol.1200119 The Journal of Immunology Three-Dimensional Visualization of the Mouse Thymus Organization in Health and Immunodeficiency Magali Irla,1 Jeanne Guenot, Gregg Sealy, Walter Reith,1 Beat A. Imhof,1 and Arnauld Serge´1 Lymphoid organs exhibit complex structures tightly related to their function. Surprisingly, although the thymic medulla constitutes a specialized microenvironment dedicated to the induction of T cell tolerance, its three-dimensional topology remains largely elusive because it has been studied mainly in two dimensions using thymic sections.
    [Show full text]
  • Multiple Inflammatory Cytokine-Productive Thyl-6 Cell Line Established from a Patient with Thymic Carcinoma
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Community Repository of Fukui Multiple Inflammatory Cytokine-Productive ThyL-6 Cell Line Established from a Patient with Thymic Carcinoma Kunihiro Inai 1, Kazutaka Takagi 2, Nobuo Takimoto 1, Hiromi Okada 1, Yoshiaki Imamura 3, Takanori Ueda 2, Hironobu Naiki 1, and Sakon Noriki 4 1 Division of Molecular Pathology, Department of Pathological Sciences, 2 Division of Hematology and Cardiology, Department of General Medicine, 3 Division of Surgical Pathology and 4 Division of Tumor Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan Corresponding author: Kazutaka Takagi, M.D. 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui 910-1193, Japan Phone: +81-776-61-3111, ext. 2296 Fax: +81-776-61-8109 E-mail: [email protected] Running title: Inflammatory Cytokine Productive ThyL-6 Cell 1 Summary Thymic epithelial cells can produce many kinds of cytokines, and interleukin (IL)-6-producing thymic carcinoma cases have been reported. However, a cytokine-producing human thymic tumor cell line has not previously been established. In this paper, we report a novel, multiple inflammatory cytokine-productive cell line that was established from a patient with thymic carcinoma. This cell line, designated ThyL-6, positively expressed epithelial membrane antigen, cytokeratins, vimentin intermediate filament, and CD5, although hematological markers were not present in the cells. Cytokine antibody array analysis showed that the cells secreted several cytokines including IL-1α, IL-6, IL-8, RANTES, soluble TNFα-receptor 1, VEGF, and CTLA into the culture medium.
    [Show full text]
  • NF-(Kappa)B Activation in Adhesion-Mediated TEC Survival
    Journal of Cell Science 113, 169-177 (2000) 169 Printed in Great Britain © The Company of Biologists Limited 2000 JCS0310 Lymphoid adhesion promotes human thymic epithelial cell survival via NF-κB activation Maria T. Scupoli1,*, Emma Fiorini1, Pier C. Marchisio2,3, Ornella Poffe1, Elda Tagliabue4, Monica Brentegani5, Giuseppe Tridente1,5 and Dunia Ramarli1,5 1Department of Pathology, Section of Immunology, University of Verona, 37134 Verona, Italy 2DIBIT, Department of Biological and Technological Research, San Raffaele Scientific Institute, 20132 Milano, Italy 3Department of Biomedical Sciences and Human Oncology, University of Torino, 10126 Torino, Italy 4Oncologia Sperimentale E-Istituto Nazionale Tumori, Milano, Italy 5Clinical Immunology, Azienda Ospedaliera Verona, 37134 Verona, Italy *Author for correspondence (e-mail: [email protected]) Accepted 27 October; published on WWW 9 December 1999 SUMMARY Inside the thymus, thymic epithelial cells and thymocytes analysis. The activation of NF-κB was necessary to promote show an interdependent relationship for their functional survival, since its inhibition by acetyl salicylic acid differentiation and development. As regards possible prevented the promoting effect. The mAb-mediated interdependency for their mutual survival, it is clear that crosslinking of α3β1 was considered as a potential inducer lympho-epithelial adhesion can control the survival of of TEC survival, since we have previously demonstrated developing thymocytes whereas the effects of lymphoid that the engagement of this integrin was able to induce NF- adhesion on epithelial cell survival have never been κB activation in TEC. The crosslinking of α3β1, which described. To address this issue, we performed co-cultures clustered at the lympho-epithelial contact sites, partially between normal human thymic epithelial cells (TEC) and reproduced the promoting activity of cell adhesion.
    [Show full text]
  • How Do Thymic Epithelial Cells Die?
    Cell Death & Differentiation (2018) 25:1002–1004 https://doi.org/10.1038/s41418-018-0093-8 CORRESPONDENCE How do thymic epithelial cells die? 1,2,4 3 1,2 1,2 1,2 1,2 Reema Jain ● Justine D. Mintern ● Iris Tan ● Grant Dewson ● Andreas Strasser ● Daniel H. D. Gray Received: 9 January 2018 / Revised: 14 February 2018 / Accepted: 19 February 2018 / Published online: 16 March 2018 © ADMC Associazione Differenziamento e Morte Cellulare 2018 Dear Editor, mice had normal thymic cellularity, TEC numbers, cortical Thymic epithelial cells (TECs) orchestrate the differ- TEC (cTEC), and mTEC subset composition (Fig. 1a, entiation of haematopoietic precursors into functional and Figure S1A). AIRE− cells were reduced in Atg7ΔFoxn1 mice self-tolerant T cells. TECs are surprisingly dynamic, with a (Fig. 1a), implying a pro-survival role for autophagy in this high proliferative rate (~8-10% per day) capable of repla- subset; however, overall these data suggest that autophagy cing the entire compartment in approximately 2 weeks does not induce TEC death. [1, 2]. These findings imply similarly high rates of TEC RNA sequencing data from TEC subsets [3] revealed death during homeostasis, yet the mechanisms and impact expression of mediators of the death receptor pathway of of cell death processes upon age-related thymic involution apoptosis (e.g. FAS, TRAIL-R, FADD, and caspase-8). 1234567890();,: are unknown. We recently found that loss of the pro- Therefore, we deleted an essential transducer of this path- survival BCL-2 family member, MCL-1, provoked abnor- way, caspase-8, specifically in TECs (Western blotting mal TEC death, and thymic atrophy [3].
    [Show full text]
  • Intrathymic Selection and Defects in the Thymic Epithelial Cell Development
    cells Review Intrathymic Selection and Defects in the Thymic Epithelial Cell Development 1,2, 1,2, 1,2, Javier García-Ceca y, Sara Montero-Herradón y and Agustín G. Zapata * 1 Department of Cell Biology, Faculty of Biology, Complutense University of Madrid, 28040 Madrid, Spain; [email protected] (J.G.-C.); [email protected] (S.M.-H.) 2 Health Research Institute, Hospital 12 de Octubre (imas12), 28041 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-91-394-4979 These authors contribute equally to the article. y Received: 7 September 2020; Accepted: 30 September 2020; Published: 2 October 2020 Abstract: Intimate interactions between thymic epithelial cells (TECs) and thymocytes (T) have been repeatedly reported as essential for performing intrathymic T-cell education. Nevertheless, it has been described that animals exhibiting defects in these interactions were capable of a proper positive and negative T-cell selection. In the current review, we first examined distinct types of TECs and their possible role in the immune surveillance. However, EphB-deficient thymi that exhibit profound thymic epithelial (TE) alterations do not exhibit important immunological defects. Eph and their ligands, the ephrins, are implicated in cell attachment/detachment and govern, therefore, TEC–T interactions. On this basis, we hypothesized that a few normal TE areas could be enough for a proper phenotypical and functional maturation of T lymphocytes. Then, we evaluated in vivo how many TECs would be necessary for supporting a normal T-cell differentiation, concluding that a significantly low number of TEC are still capable of supporting normal T lymphocyte maturation, whereas with fewer numbers, T-cell maturation is not possible.
    [Show full text]
  • Foxn1 Maintains Thymic Epithelial Cells to Support T-Cell Development Via Mcm2 in Zebra Fish
    Foxn1 maintains thymic epithelial cells to support T-cell development via mcm2 in zebrafish Dongyuan Ma1, Lu Wang1, Sifeng Wang1, Ya Gao, Yonglong Wei, and Feng Liu2 State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China Edited by Max D. Cooper, Emory University, Atlanta, GA, and approved November 7, 2012 (received for review September 30, 2012) The thymus is mainly comprised of thymic epithelial cells (TECs), for the specification of lymphoid progenitors toward the T-cell which form the unique thymic epithelial microenvironment essential lineage (18, 19). However, other Foxn1-regulated downstream for intrathymic T-cell development. Foxn1, a member of the forkhead target genes have not yet been reported. transcription factor family, is required for establishing a functional To investigate the function of foxn1 during the development of thymic rudiment. However, the molecular mechanisms underlying thymus and T cells, we have used the zebrafish model to knock the function of Foxn1 are still largely unclear. Here, we show that down foxn1 expression by using antisense morpholinos (MO). Foxn1 functions in thymus development through Mcm2 in the Our data show that foxn1-deficient embryos display impaired zebrafish. We demonstrate that, in foxn1 knockdown embryos, expression of T-cell markers, whereas the expression of early TEC the thymic rudiment is reduced and T-cell development is im- progenitor markers remains relatively unchanged. Expression pro- paired. Genome-wide expression profiling shows that a number filing and functional analysis demonstrate that, besides the pre- of genes, including some known thymopoiesis genes, are dys- viously reported downstream target genes (such as ccl25) in medaka regulated during the initiation of the thymus primordium and and mice, a unique foxn1-mcm2 axis plays a pivotal role during immigration of T-cell progenitors to the thymus.
    [Show full text]