CV Science

Magali IRLA PhD in Immunology, HDR

Course and current status

Current position: Group leader,  "Immune tolerance and T cell differentiation", Center of Immunology Marseille-Luminy (CIML), France

Contact: Magali.Irla@inserm.fr

2019: Laureate of the French National Academy of Medicine

2016:  Habilitation à Diriger des Recherches (HDR)

Since 2013: Prinicpal Investigator (Marie Curie Reintegration grant); Center of Immunology Marseille-Luminy (CIML), France

Project: "Immunological tolerance: implication of thymic epithelial cells and regulatory T cells"

2010-2012:  Junior group leader, Ambizione Fellow (Swiss National Science Foundation) - Department of Pathology and Immunology - University of Geneva Medical School, Switzerland. http://pathology.unige.ch/group-irla.html

Project: “Patterning and homeostasis of the thymic medulla, a microenvironment specialized in T cell tolerance induction”

2006-2010:   Postdoctoral fellow (EMBO Long Term fellow), Pr. Walter Reith’s laboratory - Department of Pathology and Immunology - University of Geneva Medical School, Switzerland

Project: “Cellular and molecular mechanisms controlling the cellularity of Aire⁺ medullary thymic epithelial cells - key mediators of central T cell tolerance”

2001-2005:   Ph.D. in Immunology, Dr. Catherine Nguyen’s laboratory - INSERM-U928 - University of Aix-Marseille II, France

Project:  “Genomic and functional characterization of a gene expressed by thymic epithelial cells: Spatial”

2001:  Master in Immunology, University of Aix-Marseille II

Scientific summary

Magali Irla has a long-standind interest in understanding the mechanisms controlling the induction of T-cell tolerance in the thymus. The thymic medulla provides a specialized microenvironment dedicated for T-cell education. In particular, medullary thymic epithelial cells (mTECs) play a central role in this process by their unique capacity to activate a promiscuous gene-expression program leading to the synthesis of a large repertoire of peripheral self-antigens. This gene expression program is controlled by the Autoimmune Regulator (Aire), a transcription factor that is defective in the human disease autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED).

Her work has established that the cellularity of mTECs expressing Aire is controlled by antigen specific interactions with CD4⁺ thymocytes (Immunity 2008, Trends Immunol 2010). She further established that these interactions regulate the expansion and patterning of the thymic medulla (Front Immunol. 2015, J Immunol. 2013, PLoS One. 2012). In the context of these interactions, she showed that the cytokine lymphotoxin α fine-tunes the thymic entry of peripheral dendritic cells and macrophages, which regulates central tolerance (Nat. Commun 2018). She recently found that TGF-β signaling in thymocytes is crucial for efficient negative selection (Nat. Commun 2019). She also demonstrated the regenerative potential of the cytokine RANKL to restore thymic functions upon bone marrow transplantation (EMBO Mol Med 2017).

Finally, she extended her interest in the field of T-cell tolerance by studying the mechanisms controlling the maintenance of peripheral T-cell tolerance, with a particular emphasis on the role of plamacytoid dendritic cells (pDCs). She found that pDCs, via their ability to present Ags to CD4⁺ T cells, confer a natural protection against autoimmune disease development and thus can determine the outcome of adaptive immune responses in vivo (J Exp Med. 2010).

Current research interests:

• Axis 1: Transcriptional and epigenetic programs that sustain the biology of medullary thymic epithelial cells. Although others and we have shown that mTEC differentiation in the postnatal thymus is controlled by developing CD4⁺ thymocytes through RANK and CD40 axes, much remains to be investigated in this regard. We are currently studying the molecular and epigenetic mechanisms that drive mTEC differentiation using genome-wide approaches. The identification of these mechanisms could find applications for protecting from the development of autoimmune disorders.

This project is supported by a Marie Curie reintegration Grant from the European  Commission - SIGNEPI4TOL project.

• Axis 2: Exploring the regenerative potential of cytokines to restore thymic functions. We are studying the mechanisms that drive the regeneration of TECs, which is critical to sustain de novo T-cell production notably after bone marrow transplantation. The recovery of a fully competent T-cell compartment is a prolonged process compared to that of myeloid, NK or B cells. Thus, understanding the mechanisms that control TEC regeneration is of clinical interest to boost T-cell reconstitution and thus to prevent a period of compromised immunity after cytoablative treatments. 

In this context, we recently identified that RANKL is naturally upregulated in the thymus during the early phase of thymic regeneration. The in vivo neutralization of RANKL impairs TEC recovery whereas ex vivo RANKL administration during bone marrow transplantation boosts thymic regeneration and T-cell production (EMBO Mol Med. 2017).

This project is supported by the ANR (Coordinator of the PRC, RANKLthym). 

• Axis 3: Studying the suppresive activity of regulatory T cells. We are investigating the molecular mechanisms that regulate the suppressive activity of Foxp3+ regulatory T cells (Tregs) that are critical for the maintenance of peripheral T-cell tolerance. We aim at identifying new molecules that control the regulatory properties of Tregs, which is of special interest to treat autoimmune and inflammatory disorders by Treg cell based therapies. 

This project is supported by The Foundation ARC, a Proof of Concept funding from Inserm-Transfert and Fondation A*Midex prematuration.

Other activities:

- Since 2017-present: Review Editor, Frontiers in Immunology, “Section Alloimmunity and Transplantation”

- Since 2015-present: Review Editor, Frontiers in Immunology, “Section Immunological Tolerance and Regulation”

- Since 2013-present: Associate Editorial Board member, American Journal of Clinical and Experimental Immunology

Selected publications:

• Lopes N, Boucherit N, Santamaria JC, Provin N, Charaix J, Ferrier P, Giraud M and Irla M. Thymocytes trigger self-antigen controlling pathways in immature medullary thymic epithelial stages. Elife. 2022 Feb 21;11:e69982.

• McCarron MJ*, Irla M*, Sergé A, Soudja SM, Marie JC. Transforming Growth Factor-beta signaling in αβ thymocytes promotes negative selection. Nat Commun. 2019 Dec 19;10(1):5690. *Equal contribution

• Lopes N, Charaix J, Cédile O, Sergé A and Irla M. Lymphotoxin α fine-tunes T cell clonal deletion by regulating thymic entry of antigen-presenting cells. Nat Commun. 2018 Mar 28;9(1):1262.

• Lopes N, Vachon H, Marie J and Irla M. Administration of RANKL boosts thymic regeneration upon bone marrow transplantation. EMBO Mol Med. 2017 Apr 28. pii: e201607176.

• Lopes N, Sergé A, Ferrier P and Irla M. Thymic Crosstalk Coordinates Medulla Organization and T-Cell Tolerance Induction. Front Immunol. 2015 Jul 20;6:365.

• Emre Y, Irla M, Dunand-Sauthier I, Ballet R, Meguenani M,Jemelin S, Vesin C, Reith W, and Imhof B. Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output. Nat. Commun. 2013; 4:2842. 

• Irla M*, Guenot J, Sealy G, Reith W, Imhof BA, Sergé A*. Three-dimensional visualization of the mouse thymus organization in health and immunodeficiency. J Immunol. 2013 Jan 15;190(2):586-96. *Co-corresponding author.

• Irla M, Kupfer N, Benkhoucha M, Lalive P, Suter T, Fontana A, and Reith W* and Hugues S*. MHC class II restricted antigen presentation by plasmacytoid dendritic cells inhibits T-cell mediated autoimmunity. J Exp Med. 2010 Aug 30;207(9):1891-905.* co-authors.

• Irla M, Holländer GA, Reith W. Control of central self-tolerance induction by autoreactive CD4⁺ thymocytes. Trends Immunol. 2010 Feb;31(2):71-79. 

• Irla M, Hugues S, Gill J, Nitta T, Hikosaka Y, Williams IR, Hubert FX, Scott HS, Takahama Y, Holländer GA, Reith W. Autoantigen-specific interactions with CD4⁺ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity. 2008;29(3):451-63.

Commentaries and previews on published work:

• Passos GA, Mendes-da-Cruz DA, Oliveira EH. Editorial: The Role of Aire, microRNAs and Cell–Cell Interactions on Thymic Architecture and Induction of Tolerance. Front Immunol. 2015 Dec 14;6:615. 

• Bordon Y. Immune tolerance: Present and clear danger. Nat Rev Immunol. 2010 Sep;10(9):616. 

• Zhu M, Fu YX. Coordinating Development of Medullary Thymic Epithelial Cells. Immunity. 2008, Vol. 29, Issue 3, p386–388.

 

Other links:

http://www.ciml.univ-mrs.fr/science/lab-magali-irla/immune-tolerance-and-t-cell-differentiation

https://loop.frontiersin.org/people/83580/impact

https://www.researchgate.net/profile/Magali_Irla

https://orcid.org/0000-0001-8803-9708