CV Science

Magali IRLA Team leader, PhD in Immunology, HDR

Course and current status

Current position: 

Research Director (DR2), INSERM

Team leader,  "Immune tolerance and T cell differentiation", Center of Immunology Marseille-Luminy (CIML), France

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

Contact: Magali.Irla@inserm.fr

Since 2022: Member of the scientific panel "Immunology, Microbiology, Infection" (CSS5), INSERM

Education and academic positions:

2013-2020: Prinicpal Investigator, CR1 INSERM (Marie Curie Reintegration grant, SIGNEPI4TOL); Center of Immunology Marseille-Luminy (CIML), France

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

2016:  Habilitation à Diriger des Recherches (HDR)

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

Prizes and Awards:

2019-2022       PEDR - Inserm
2019                Laureate of the French National Academy of Medicine
2015-2019       Marie Curie Career Integration Grant
2014                Installation Award - City of Marseille
2012                Young Investigator Award - International Cytokine Society (ICS)
2011                Young Investigator Award - French Society for Immunology (SFI)
2010                Biogen-Dompé Award - Swiss Multiple Sclerosis Society
2006-2007       EMBO long-term fellowship
2004                Laureate of Innovact Awards for European Innovation 

Editorial activities:

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

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

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

Scientific summary

Magali Irla has a long-standind interest in understanding the mechanisms controlling the induction of T-cell tolerance in the thymus (Annu Rev Immunol 2022). 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). These interactions induce the expansion and patterning of the thymic medulla by regulating the transcriptional and epigenetic profile of mTECs (Elife 2022, Front Immunol. 2015, J Immunol. 2013). In the context of these interactions, her team has shown that the cytokine lymphotoxin α fine-tunes the thymic entry of peripheral dendritic cells and macrophages, which regulates central tolerance (Nat. Commun 2018). Lymphotoxin also acts as an inhibitory checkpoint for the thymic development of Foxp3⁺ Tregs from the Foxp3^lo precursor pathway via IL-4 signaling (Nat. Commun 2024). Moreover, TGF-β signaling in thymocytes is crucial for Aire⁺ mTEC differentiation and efficient negative selection (Nat. Commun 2019). In a therapeutic perspective, her team has demonstrated the regenerative potential of the cytokine RANKL to restore the thymic function 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).

Selected publications:

• Borelli A, Santamaria JC, Zamit C, Apert C, Chevallier J, Pierre P, Argüello RJ, Spinelli L and Irla M. Lymphotoxin limits Foxp3+ regulatory T cell development from Foxp3lo precursors via IL-4 signaling. Nat Commun. 2024 Aug 14;15(1):6976.
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• Irla M. Instructive Cues of Thymic T Cell Selection. Annu Rev Immunol. 2022 Apr 26;40:95-119.

• 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.

• Borelli A, Irla M. Lymphotoxin: from the physiology to the regeneration of the thymic function. Cell Death Differ. 2021. 28(8) 2305-2314.
  

• 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

https://mobile.twitter.com/irlalab (@IrlaLab)