Project

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Role of medullary thymic epithelial cells in the generation of natural regulatory T cells

Applicant Irla Magali
Number 131945
Funding scheme Ambizione
Research institution Centre d’Immunologie de Marseille-Luminy
Institution of higher education University of Geneva - GE
Main discipline Immunology, Immunopathology
Start/End 01.01.2011 - 31.12.2013
Approved amount 471'323.30
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Keywords (8)

Immunological self-tolerance; thymus; regulatory T cells; autoimmune diseases; medullary thymic epithelial cells; cortical thymic epithelial cells; dendritic cells; knockout and transgenic mouse models

Lay Summary (English)

Lead
Lay summary
Healthy individuals mount immune responses directed against pathogens while avoiding autoimmune attacks on their own tissues. This ability to distinguish between self and non-self is referred to as immunological self-tolerance. Natural regulatory T (nTreg) cells are pivotal players in the maintenance of immunological self-tolerance because they possess the unique property of being able to prevent autoimmunity by suppressing the activation of autoreactive T lymphocytes. Deficiencies in nTreg cells consequently lead to severe autoimmunity in humans and mice. Although, the importance of nTreg cells in the immune system is well recognized, the molecular and cellular mechanisms governing their generation in the thymus remain unsolved. In particular, the precise identities of the stromal cells that promote and support nTreg development in the thymus remain unclear. The aim of this proposal is to define the respective contributions of different thymic stromal cells to nTreg development. One goal of the proposal is to determine the contribution of medullary thymic epithelial cells. These cells constitute attractive candidates because they express a broad range of peripheral tissue-restricted self-antigens that may be of particular relevance for the generation of an nTreg population. Another goal is to extend this study to other thymic stromal cells. The respective contributions of cortical thymic epithelial cells and thymic dendritic cells will be in particular analyzed. Taken together, the anticipated results will highlight the nature of the thymic stromal cells that drive the generation of nTreg cells, thereby furthering our knowledge on the mechanisms that establish and maintain immunological self-tolerance.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Three-dimensional visualization of the mouse thymus organization in health and immunodeficiency
IRLA Magali, GUENOT Jeanne, SEALY Gregg, REITH Walter, IMHOF Beat, SERGE Arnauld (2013), Three-dimensional visualization of the mouse thymus organization in health and immunodeficiency, in The Journal of Immunology, 190(2), 586-596.
Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output.
Emre Yalin, Irla Magali, Dunand-Sauthier Isabelle, Ballet Romain, Meguenani Mehdi, Jemelin Stephane, Vesin Christian, Reith Walter, Imhof Béat (2013), Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output., in Nature Communications, 4, 2842.
Antigen recognition by autoreactive cd4(+) thymocytes drives homeostasis of the thymic medulla
IRLA Magali, GUERRI Lucia, GUENOT Jeanne, SERGE Arnauld, LANTZ Olivier, LISTON Adrian, IMHOF Beat, PALMER Ed, REITH Walter (2012), Antigen recognition by autoreactive cd4(+) thymocytes drives homeostasis of the thymic medulla, in PLoS One, 7(12), e52591.

Collaboration

Group / person Country
Types of collaboration
University Hospital of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Autoimmune Genetics Laboratory, VIB and University of Leuven Belgium (Europe)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Division of Developmental Immunology, German Cancer Research Center (DKFZ) Individual talk 13.12.2013 Heidelberg, Germany Irla Magali;
Centre Leon Bérard-Seminars Individual talk 28.06.2013 Lyon, France Irla Magali;
6th Workshop of Kyoto T Cell Conference (KTCC2013) Talk given at a conference 03.06.2013 Kyoto, Japan Irla Magali; Serge Arnauld;
10th Joint Annual Meeting Cytokines 2012 Poster 11.09.2012 Geneve, Suisse, Switzerland Irla Magali;
European Congress of Immunology (ECI) Talk given at a conference 05.09.2012 Glasgow, Ecosse, Great Britain and Northern Ireland Irla Magali;
Annual Meeting of the French Society for Immunology (SFI) Talk given at a conference 07.11.2011 Montpellier, France, France Irla Magali;
European Thymus Workshop Poster 21.05.2011 Noordwijkerhout, Netherlands, Netherlands Irla Magali;


Awards

Title Year
Installation Grant - City of Marseille 2013
Young Investigator Award (1st prize)-International Cytokine Society (ICS) 2012
Young Investigator Award - French Society for Immunology (SFI), 2011 2011

Abstract

Natural regulatory T (nTreg) cells are pivotal players in the maintenance of immunological self-tolerance because they possess the unique property of preventing autoimmunity by suppressing the activation of autoreactive T lymphocytes. Deficiencies in nTreg cells consequently lead to severe autoimmunity in humans and mice. nTreg belong mainly to the CD4+ T cell lineage. The transcription factor Foxp3 is essential for their development and function, and constitutes a highly specific marker for identifying these cells. Foxp3+ CD4+ nTreg develop in the thymus. It is well established that their selection requires high-affinity interactions between their T cell receptors (TCR) and self-antigen-MHC class II (MHCII) complexes displayed at the surface of thymic stromal cells. It has also been shown that nTreg development requires the engagement of T cell costimulatory molecules on the stromal cells. However, the precise identities of the stromal cells that promote and support nTreg development in the thymus remain unclear. The aim of the project outlined here is therefore to define the respective contributions of different thymic stromal cells to nTreg development. I will in particular focus on the role of mature medullary thymic epithelial cells (mTEC). Mature mTEC constitute attractive candidates because they express high levels of MHCII molecules, costimulatory molecules known to be implicated in nTreg development, and a broad range of peripheral tissue-restricted self-antigens (TRA). TRA expression by mTEC may be of particular relevance for the generation of an nTreg population having a diverse autoreactive TCR repertoire. To attain these objectives I will exploit recently generated mice that lack MHCII expression specifically by mTEC and consequently exhibit a strong reduction in the number of mature mTEC. These mice will be used to study the role of mTEC in the generation of nTreg cells. In addition, they will be used to generate bone marrow chimeric mice that will permit us to define the contributions of cortical thymic epithelial cells (cTEC) and thymic dendritic cells (DC) to nTreg development. Taken together, the anticipated results will highlight the nature of the thymic stromal cells that drive the generation of nTreg cells, thereby furthering our knowledge on the mechanisms that establish and maintain immunological self-tolerance.
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