Magali Irla

Magali Irla
Centre d'Immunologie de Marseille-Luminy | CIML

PhD, HDR, Principal investigator

About

81
Publications
6,060
Reads
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1,173
Citations
Additional affiliations
January 2013 - present
Centre d'Immunologie de Marseille-Luminy
Position
  • Principal Investigator
January 2006 - December 2012
University of Geneva
Position
  • PostDoc Position

Publications

Publications (81)
Article
Full-text available
Thymically-derived Foxp3⁺ regulatory T cells (Treg) critically control immunological tolerance. These cells are generated in the medulla through high affinity interactions with medullary thymic epithelial cells (mTEC) expressing the Autoimmune regulator (Aire). Recent advances have revealed that thymic Treg contain not only developing but also reci...
Article
A high diversity of αβ T cell receptors (TCRs), capable of recognizing virtually any pathogen but also self-antigens, is generated during T cell development in the thymus. Nevertheless, a strict developmental program supports the selection of a self-tolerant T cell repertoire capable of responding to foreign antigens. The steps of T cell selection...
Article
Full-text available
Interactions of developing T cells with Aire+ medullary thymic epithelial cells expressing high levels of MHCII molecules (mTEChi) are critical for the induction of central tolerance in the thymus. In turn, thymocytes regulate the cellularity of Aire+ mTEChi. However, it remains unknown whether thymocytes control the precursors of Aire+ mTEChi that...
Article
Aire allows medullary thymic epithelial cells (mTECs) to express and present a large number of self-antigens for central tolerance. Although mTECs express a high diversity of self-antigen splice isoforms, the extent and regulation of alternative splicing events (ASEs) in their transcripts, notably in those induced by Aire, is unknown. In contrast t...
Article
In type 1 diabetes, autoimmune β-cell destruction may be favored by neo-antigens harboring post-translational modifications such as citrullination. We studied the recognition of native and citrullinated glucose-regulated protein (GRP)78 peptides by CD8+ T cells. Citrullination modulated T-cell recognition and, to a lesser extent, HLA-A2 binding. GR...
Article
Full-text available
Follicular T helper cells (Tfh) are a specialized subset of CD4 effector T cells that are crucial for germinal center (GC) reactions and for selecting B cells to undergo affinity maturation. Despite this central role for humoral immunity, only few data exist about their clonal distribution when multiple lymphoid organs are exposed to the same antig...
Article
The members of the Tumor Necrosis Factor (TNF) superfamily, the ligand lymphotoxin α1β2 (LTα1β2) and its unique receptor lymphotoxin β receptor (LTβR), play a pivotal role in the establishment and regulation of the immune system by allowing a tight communication between lymphocytes and stromal cells. Recent advances using transgenic mice harboring...
Preprint
Full-text available
Aire allows medullary thymic epithelial cells (mTECs) to express and present a large number of self-antigens for central tolerance. Although mTECs express a high diversity of self-antigen splice isoforms, the extent and regulation of alternative splicing events (ASEs) included in their transcripts, notably in those induced by Aire, is unknown. Unex...
Article
Full-text available
Foxp3+ regulatory T cells (Treg) maintain the integrity of the organism by preventing excessive immune responses. These cells protect against autoimmune diseases but are also important regulators of other immune responses including inflammation, allergy, infection, and tumors. Furthermore, they exert non-immune functions such as tissue repair and r...
Article
Full-text available
Thymic epithelial cells (TECs) provide essential clues for the proliferation, survival, migration, and differentiation of thymocytes. Recent advances in mouse and human have revealed that TECs constitute a highly heterogeneous cell population with distinct functional properties. Importantly, TECs are sensitive to thymic damages engendered by myeloa...
Preprint
Interactions of developing T cells with Aire ⁺ medullary thymic epithelial cells expressing high levels of MHCII molecules (mTEC hi ) are critical for the induction of central tolerance. In turn, thymocytes regulate the cellularity of Aire ⁺ mTEC hi . However, it remains unknown whether thymocytes control Aire ⁺ mTEC hi -precursors that are contain...
Article
Full-text available
In the thymus, the T lymphocyte repertoire is purged of a substantial portion of highly self-reactive cells. This negative selection process relies on the strength of TCR-signaling in response to self-peptide-MHC complexes, both in the cortex and medulla regions. However, whether cytokine-signaling contributes to negative selection remains unclear....
Article
Full-text available
Systemic lupus erythematosus (SLE) patients have increased prevalence of metabolic syndrome but the underlying mechanisms are unknown. Toll-like receptor 7 (TLR7) that detects single stranded-RNA plays a key role in antimicrobial host defense and also contributes to the initiation and progression of SLE both in mice and humans. Here, we report the...
Article
Background: Patients with T-cell immunodeficiencies are generally treated with allogeneic hematopoietic stem cell transplantation, but alternatives are needed for patients without matched donors. An innovative intrathymic gene therapy approach that directly targets the thymus might improve outcomes. Objective: We sought to determine the efficacy...
Chapter
The thymus ensures the generation of a self-tolerant T-cell repertoire capable of recognizing foreign antigens. The selection of the T-cell repertoire is dictated by the thymic microenvironment. Among stromal cells, medullary thymic epithelial cells (mTECs) play a pivotal role in this process through their unique ability to express thousands of tis...
Article
Full-text available
Medullary thymic epithelial cells (mTEC) purge the T cell repertoire of autoreactive thymocytes. Although dendritic cells (DC) reinforce this process by transporting innocuous peripheral self-antigens, the mechanisms that control their thymic entry remain unclear. Here we show that mTEC-CD4+thymocyte crosstalk regulates the thymus homing of SHPS-1+...
Article
Full-text available
Regulatory T cells (Tregs) restrict overexuberant lymphocyte activation. While close proximity between Tregs and their suppression targets is important for optimal inhibition, and literature indicates that draining lymph nodes (LNs) may serve as a prime location for the suppression, signaling details orchestrating this event are not fully character...
Article
Full-text available
Cytoablative treatments lead to severe damages on thymic epithelial cells (TECs), which result in delayed de novo thymopoiesis and a prolonged period of T-cell immunodeficiency. Understanding the mechanisms that govern thymic regeneration is of paramount interest for the recovery of a functional immune system notably after bone marrow transplantati...
Article
Full-text available
Plasmacytoid dendritic cells (pDCs) have been shown to both mediate and prevent autoimmunity, and the regulation of their immunogenic versus tolerogenic functions remains incompletely understood. Here we demonstrate that, compared to other cells, pDCs are the major expressors of Indoleamine-2,3-dioxygenase (IDO) in steady-state lymph nodes (LNs). I...
Article
Full-text available
The establishment of thymic central tolerance is a critical process to prevent the development of autoimmune diseases. Medullary thymic epithelial cells (mTEC) are essential to this process through the expression of the transcription factor Aire, which controls the transcription of many genes encoding tissue-restricted antigens. Mutations in the Ai...
Article
Full-text available
The thymus ensures the generation of a functional and highly diverse T-cell repertoire. The thymic medulla, which is mainly composed of medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), provides a specialized microenvironment dedicated to the establishment of T-cell tolerance. mTECs play a privileged role in this pivotal process...
Article
Full-text available
Plasmacytoid dendritic cells (pDCs) rapidly and massively produce type I interferon and other inflammatory cytokines in response to foreign nucleic acids, thereby indirectly influencing adaptive T cell responses. Moreover, pDCs present Ag to naïve T cells and directly regulate T cell differentiation. Depending on the immune environment, pDCs exhibi...
Article
Thymic epithelial cells (TEC) and dendritic cells (DC) play a role in T cell development by controlling the selection of the T cell receptor repertoire. DC have been described to take up antigens in the periphery and migrate into the thymus where they mediate tolerance via deletion of autoreactive T cells, or by induction of natural regulatory T ce...
Article
Full-text available
Arginine, a semiessential amino acid implicated in diverse cellular processes, is a substrate for two arginases-Arg1 and Arg2-having different expression patterns and functions. Although appropriately regulated Arg1 expression is critical for immune responses, this has not been documented for Arg2. We show that Arg2 is the dominant enzyme in dendri...
Article
Full-text available
αβT cell development depends upon serial migration of thymocyte precursors through cortical and medullary microenvironments, enabling specialized stromal cells to provide important signals at specific stages of their development. Although conventional αβT cells are subject to clonal deletion in the medulla, entry into the thymus medulla also foster...
Article
Full-text available
B cells play a major role in the pathogenesis of many autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and type I diabetes mellitus, as indicated by the efficacy of B cell-targeted therapies in these diseases. Therapeutic effects of the most commonly used B cell-targeted therapy, anti-CD20 mAb,...
Article
Thymic epithelial cells (TEC) are heterogeneous stromal cells that generate microenvironments required for the formation of T cells within the thymus. Defects in TEC lead to immunodeficiency or autoimmunity. Here we identify TEC as the major source of cysteine-rich protein 61 (CYR61), a matricellular protein implicated in cell proliferation and mig...
Article
Full-text available
Video-microscopy allows monitoring the dynamics of biological components, specifically labeled, usually by fluorescent tags such as GFP or quantum dots, either at the cellular or at the molecular scale. Reconstructing trajectories over time with dedicated algorithms allows to characterize on both scale different categories of movement, such as rand...
Article
Full-text available
The thymic medulla is dedicated for purging the T-cell receptor (TCR) repertoire of self-reactive specificities. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process because they express numerous peripheral tissue-restricted self-antigens. Although it is well known that medulla formation depends on the development of single...
Data
mTECs but not DCs are impaired in mice lacking CD4+ thymocytes. (A) Representative FACS profiles for the expression of Aire and CD80 by CD45−EpCAM+Ly51−/lo mTECs from WT, β2m−/−, H2-Aα−/− and CIItaIV-/IV- mice: numbers represent the percentages of cells within the indicated gates. Graphs show number of Aire+, CD80hi, CD80int and CD80lo mTECs: the m...
Data
Injection of the cognate peptide induces expansion of the thymic medulla in OTII:Rag2−/− mice and female Marilyn:Rag2−/− mice. (A) OTII:Rag2−/− mice were injected i.v with PBS or OVA323–339. 5 days later, 3D reconstructions of thymic lobes were generated from serial sections stained with antibodies against K14 and DAPI. 3D reconstructions depicting...
Data
Restoration of thymic medulla formation in Rag2−/− TCR transgenic mice by i.v injection of the cognate Ag. (A) Thymic sections from OTII:Rag2−/− mice injected with PBS or OVA323–339 were stained with antibodies against MTS10: m and c denote the medulla and cortex. The graph shows quantifications of MTS10+ medullary areas: data is pooled from three...
Data
3D reconstruction of an entire thymic lobe from female Marilyn:Rag2−/− mouse injected with PBS. Volumes were determined as described for Movie S1. (AVI)
Data
Positively-selected CD4+ thymocytes in 3BBM74:Rag2−/−, B3K508:Rag1−/− and OTII:Rag2−/− are inefficient at inducing medulla expansion whereas low numbers of autoreactive CD4+ thymocytes are sufficient. (A) Thymic sections from 3BBM74:Rag2−/−, B3K508:Rag1−/−, OTII:Rag2−/− and WT mice were stained with antibodies against K8 and K14: m denotes the medu...
Data
3D reconstruction of an entire thymic lobe from OTII:Rag2−/− mouse injected with the OVA323–339 peptide. Volumes were determined as described for Movie S1. (AVI)
Data
3D reconstruction of an entire thymic lobe from OTII:Rag2−/− mouse injected with PBS. Thymic and medullary volumes were reconstructed using a whole thymic lobe. 20 µm thick serial sections were stained with DAPI (light blue) and antibodies against K14 (red). Volume rendering was performed from epifluorescence images, as described in methods. All ax...
Data
3D reconstruction of an entire thymic lobe from female Marilyn:Rag2−/− mouse injected with the H-Y Dby peptide. Volumes were determined as described for Movie S1. (AVI)
Article
Full-text available
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. To overc...
Article
The thymus ensures the generation of a diverse repertoire of T lymphocytes capable of mounting immune responses directed against pathogens while avoiding autoimmune attacks directed at self-antigens. The thymic medulla provides a specialized microenvironment dedicated to purging the T-cell repertoire of potentially hazardous self-reactive specifici...
Article
Full-text available
MicroRNAs (miRNAs) are small, noncoding RNAs that regulate target mRNAs by binding to their 3' untranslated regions. There is growing evidence that microRNA-155 (miR155) modulates gene expression in various cell types of the immune system and is a prominent player in the regulation of innate and adaptive immune responses. To define the role of miR1...
Article
Full-text available
Although plasmacytoid dendritic cells (pDCs) express major histocompatibility complex class II (MHCII) molecules, and can capture, process, and present antigens (Ags), direct demonstrations that they function as professional Ag-presenting cells (APCs) in vivo during ongoing immune responses remain lacking. We demonstrate that mice exhibiting a sele...
Data
Primer sequences used for real time PCR are listed in Table S1. (0.03 MB DOC)
Data
Humoral response and complement deposition analysis of rejecting and tolerant mice. Immunohistology for humoral immune responses to concordant islet xenografts in untreated C57BL/6 mice and in combination therapy (MR1+RAPA) treated mice at 200 days post transplantation. Sections were stained by anti-mouse IgG (A/D), IgM (B/E) and complement (C3, C/...
Data
Concordant xeno- and allo-responses are diminished in late tolerant mice. White bars, naïve mice; gray bars: Group 6, (late anti-IL2 treatment); black bars: Group 8 (late anti-CD25 mAb treatment). Alternatively Sprague donor strain splenocytes, Lewis splenocytes, BALB/c splenocytes or human PBMC were used as stimulators. In late anti-IL2 mAb and la...
Article
Full-text available
Anti-CD154 (MR1) monoclonal antibody (mAb) and rapamycin (RAPA) treatment both improve survival of rat-to-mouse islet xenograft. The present study investigated the effect of combined RAPA/MR1 treatment on rat-to-mouse islet xenograft survival and analyzed the role of CD4(+)CD25(+)Foxp3(+) T regulatory cells (Treg) in the induction and maintenance o...
Article
This issue's cover image depicts thymus ontogeny in mice associated with changes in the distribution patterns of Spatial and keratins by thymic epithelial cells, taken from Saade et al. (pp. 530–538). In this article, the authors explore the expression of the Spatial gene during thymus ontogeny and in the adult thymus, and demonstrate that in the m...
Article
The Spatial gene is expressed in highly polarized cell types such as testis germ cells, brain neurons and thymic epithelial cells (TEC). Its expression was documented in testis and brain but poorly characterized in thymus. Here, we characterize for the first time Spatial-expressing TEC throughout ontogeny and adult mouse thymus. Spatial is expresse...
Article
Medullary thymic epithelial cells (mTECs) are crucial for the selection of a T-cell-receptor (TCR) repertoire purged of self-reactive specificities, because these cells activate a promiscuous gene-expression program that leads to the synthesis of a wide array of peripheral tissue-restricted self-antigens. This review summarizes recent progress in o...
Article
Full-text available
Encounter of self-antigens in the periphery by mature T cells induces tolerance in the steady-state. Hence, it is not understood why the same peripheral antigens are also promiscuously expressed in the thymus to mediate central tolerance. Here, we analyzed CD8(+) T-cell tolerance to such an antigen constituted by ovalbumin under the control of the...
Article
Medullary thymic epithelial cells (mTECs) are specialized for inducing central immunological tolerance to self-antigens. To accomplish this, mTECs must adopt a mature phenotype characterized by expression of the autoimmune regulator Aire, which activates the transcription of numerous genes encoding tissue-restricted self-antigens. The mechanisms th...
Data
The sizes of the CDR3 were analysed by PCR followed by gel electrophoresis. The figure displays representative experiments of the CDR3 analysis of TCR transcripts for alpha chain bearing Valpha1. The relative intensity of the bands (y axis) was plotted as a function of the migration time in the electrophoresis (x axis) which is proportional to the...
Data
Analysis of the thymus after monopolar electroporation. (A) The picture shows the healthy physical state of vital organs close to the thymus after injection and electroporation. Impact points in each thymic lobe are indicated by arrows. T: Thymus, H: Heart and L: Lung. The pCMV-luc plasmid was injected (0 V) or electroporated at 300 V and the lucif...
Data
Efficacy of thymocyte transfection after in vivo thymic electroporation. (A) Characterization of transfected cells by co-staining analysis with an anti-CD3 antibody in the thymus 24 hours and one month after thymic electroporation. Insets correspond to a higher magnification of EGFP transfected CD3 positive thymocytes. (B) The histogram shows perce...