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BloodVolume 130, Issue 4, 27 July 2017, Pages 478-488

Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice(Article)(Open Access)

  • Rodrigues, P.M.,
  • Ribeiro, A.R.,
  • Perrod, C.,
  • Landry, J.J.M.,
  • Araújo, L.,
  • Pereira-Castro, I.,
  • Benes, V.,
  • Moreira, A.,
  • Xavier-Ferreira, H.,
  • Meireles, C.,
  • Alves, N.L.
  • View Correspondence (jump link)
  • aInstituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
  • bThymus Development and Function Laboratory, Instituto de Biologia Molecular e Celular, Porto, Portugal
  • cDoctoral Program in Biomedical Sciences, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
  • dGenomics Core Facility, European Molecular Biology Laboratory, Heidelberg, Germany
  • eGene Regulation Laboratory, Instituto de Biologia Molecular e Celular, Porto, Portugal
  • fInstituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal

Abstract

Thymic epithelial cells (TECs) provide crucial microenvironments for T-cell development and tolerance induction. As the regular function of the thymus declines with age, it is of fundamental and clinical relevance to decipher new determinants that control TEC homeostasis in vivo. Beyond its recognized tumor suppressive function, p53 controls several immunoregulatory pathways. To study the cell-autonomous role of p53 in thymic epithelium functioning, we developed and analyzed mice with conditional inactivation of Trp53 in TECs (p53cKO). We report that loss of p53 primarily disrupts the integrity of medullary TEC (mTEC) niche, a defect that spreads to the adult cortical TEC compartment. Mechanistically, we found that p53 controls specific and broad programs of mTEC differentiation. Apart from restraining the expression and responsiveness of the receptor activator of NF-κB (RANK), which is central for mTEC differentiation, deficiency of p53 in TECs altered multiple functional modules of the mTEC transcriptome, including tissue-restricted antigen expression. As a result, p53cKO mice presented premature defects in mTEC-dependent regulatory T-cell differentiation and thymocyte maturation, which progressed to a failure in regular and regenerative thymopoiesis and peripheral T-cell homeostasis in the adulthood. Lastly, peripheral signs of altered immunological tolerance unfold in mutant mice and in immunodeficient mice that received p53cKO-derived thymocytes. Our findings position p53 as a novel molecular determinant of thymic epithelium function throughout life. © 2017 by The American Society of Hematology.

Indexed keywords

EMTREE drug terms:protein p53receptor activator of nuclear factor kappa Btranscriptomeprotein p53
EMTREE medical terms:adultanimal cellanimal experimentanimal tissueantigen expressionArticlecell functioncell maturationcell spreadingcontrolled studyembryoepithelium cellfetusgene inactivationhomeostasisimmunological toleranceknockout mouselymphocyte differentiationmousemouse mutantnewbornnonhumanpriority journalprotein expressionregulatory T lymphocytestem cell nicheT lymphocytethymic epithelial cellthymic medullathymocytethymopoiesisanimalcell differentiationcytologyepithelium cellgeneticsimmunologythymocytethymus
MeSH:AnimalsCell DifferentiationEpithelial CellsMiceMice, KnockoutT-Lymphocytes, RegulatoryThymocytesThymus GlandTumor Suppressor Protein p53

Chemicals and CAS Registry Numbers:

Tumor Suppressor Protein p53

Funding details

Funding sponsor Funding number Acronym
POCI-01-0145-FEDER-007274
Fundação para a Ciência e a Tecnologia
See opportunities		PTDC/SAU-IMU/ 117057/2010,FCOMP-01-0124-FEDER-021075
POCI
European Regional Development Fund
Fundação Portugal Telecom
China National Funds for Distinguished Young Scientists
2020,637843-TEC_Pro
European Research Council
European Regional Development Fund
NORTE 2020

  • 1

    The authors thank Thomas Boehm (Max Planck Institute of Immunology and Epigenetics) for Foxn1-Cre mice; Rui Appelberg (I3S) and Nuno Rodrigues dos Santos (I3S) for critical reading of the manuscript; Matthias Futschik and Jos? Pedro Pinto (University of Algarve) for critical discussions; and Sofia Lamas, Rui Fernandes, Catarina Leit?o, and the caretakers from the animal facility for technical assistance. This study was supported by the European Research Council (ERC) under the European Union?s Horizon 2020 research and innovation program (grant agreement No 637843-TEC_Pro) starting grant attributed to N.L.A., by FEDER (Fundo Europeu de Desenvolvimento Regional) funds through the Operational Competitiveness Programme?COMPETE, and by National Funds through Funda??o para a Ci?ncia e a Tecnologia (FCT) under the project FCOMP-01-0124-FEDER-021075 (PTDC/SAU-IMU/ 117057/2010), by NORTE-01-0145-FEDER-000012?Structured program on bioengineered therapies for infectious diseases and tissue regeneration, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER); by FEDER funds through the COMPETE 2020?Operational Programme for Competitiveness and Interna-tionalisation (POCI), Portugal 2020, and by Portuguese funds through FCT/Minist?rio da Ci?ncia, Tecnologia e Inova??o in the framework of the project Institute for Research and Innovation in Health Sciences (POCI-01-0145-FEDER-007274). The Investigator Program and doctoral and postdoctoral fellowships from FCT support N.L.A., P.M.R., A.R.R., I.P.-C., and C.M.

  • ISSN: 00064971
  • CODEN: BLOOA
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1182/blood-2016-12-758961
  • PubMed ID: 28559356
  • Document Type: Article
  • Publisher: American Society of Hematology

  Alves, N.L.; Instituto de Investigação e Inovação em Saúde (I3S), Instituto de Biologia Molecular e Celular, Rua Alfredo Allen, 208, Porto, Portugal;
© Copyright 2017 Elsevier B.V., All rights reserved.

Cited by 5 documents

Luan, R. , Liang, Z. , Zhang, Q.
Molecular regulatory networks of thymic epithelial cell differentiation
(2019) Differentiation
Magrone, T. , Jirillo, E.
The tolerant immune system: Biological significance and clinical implications of T cell tolerance
(2019) Endocrine, Metabolic and Immune Disorders - Drug Targets
Rodrigues, P.M. , Peterson, P. , Alves, N.L.
Setting Up the Perimeter of Tolerance: Insights into mTEC Physiology
(2018) Trends in Immunology
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