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Truffault Et Al. Frontiers Imm Comparative Analysis of Thymic and Blood Treg in Myasthenia Gravis: Thymic Epithelial Cells Contribute to Thymic Immunoregulatory Defects Frédérique Truffault, Dani Nazzal, Julien Verdier, Angeline Gradolatto, Elie Fadel, Régine Roussin, Bruno Eymard, Rozen Le Panse, Sonia Berrih-Aknin To cite this version: Frédérique Truffault, Dani Nazzal, Julien Verdier, Angeline Gradolatto, Elie Fadel, et al..Com- parative Analysis of Thymic and Blood Treg in Myasthenia Gravis: Thymic Epithelial Cells Con- tribute to Thymic Immunoregulatory Defects. Frontiers in Immunology, Frontiers, 2020, 11, pp.782. 10.3389/fimmu.2020.00782. hal-02970791 HAL Id: hal-02970791 https://hal.archives-ouvertes.fr/hal-02970791 Submitted on 19 Oct 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. fimmu-11-00782 May 4, 2020 Time: 19:41 # 1 ORIGINAL RESEARCH published: 06 May 2020 doi: 10.3389/fimmu.2020.00782 Comparative Analysis of Thymic and Blood Treg in Myasthenia Gravis: Thymic Epithelial Cells Contribute to Thymic Immunoregulatory Defects Frédérique Truffault1†, Dani Nazzal1†, Julien Verdier1†, Angeline Gradolatto1†, Elie Fadel2, Régine Roussin2, Bruno Eymard3, Rozen Le Panse1* and Sonia Berrih-Aknin1 1 Sorbonne Université, INSERM, Institut de Myologie, Centre de Recherche en Myologie, Paris, France, 2 Marie Lannelongue Hospital, Le Plessis-Robinson, France, 3 AP-HP, Referral Center for Neuromuscular Disorders, Pitié-Salpêtrière Hospital, Institute of Myology, Paris, France The thymus is involved in autoimmune Myasthenia gravis (MG) associated with anti- Edited by: acetylcholine (AChR) antibodies. In MG, thymic regulatory T cells (Treg) are not efficiently Carlo Riccardi, suppressive, and conventional T cells (Tconv) are resistant to suppression. To better University of Perugia, Italy understand the specific role of the thymus in MG, we compared the phenotype and Reviewed by: function of peripheral and thymic Treg and Tconv from controls and MG patients. Socrates J. Tzartos, Pasteur Hellenic Institute, Greece Suppression assays with thymic or peripheral CD4 + T cells showed that the functional Alexander Marx, impairment in MG was more pronounced in the thymus than in the periphery. Phenotypic University of Heidelberg, Germany analysis of Treg showed a significant reduction of resting and effector Treg in the *Correspondence: Rozen Le Panse thymus but not in the periphery of MG patients. CD31, a marker lost with excessive [email protected] immunoreactivity, was significantly reduced in thymic but not blood resting Treg. These †These authors have contributed results suggest that an altered thymic environment may explain Treg differences between equally to this work MG patients and controls. Since thymic epithelial cells (TECs) play a major role in the Specialty section: generation of Treg, we co-cultured healthy thymic CD4 + T cells with control or MG This article was submitted to TECs and tested their suppressive function. Co-culture with MG TECs consistently Autoimmune and Autoinflammatory hampers regulatory activity, as compared with control TECs, suggesting that MG Disorders, a section of the journal TECs contribute to the immune regulation defects of MG CD4 + T cells. MG TECs Frontiers in Immunology produced significantly higher thymic stromal lymphopoietin (TSLP) than control TECs, Received: 16 January 2020 and a neutralizing anti-TSLP antibody partially restored the suppressive capacity of Treg Accepted: 06 April 2020 Published: 06 May 2020 derived from co-cultures with MG TECs, suggesting that TSLP contributed to the defect Citation: of thymic Treg in MG patients. Finally, a co-culture of MG CD4 + T cells with control TECs Truffault F, Nazzal D, Verdier J, restored numbers and function of MG Treg, demonstrating that a favorable environment Gradolatto A, Fadel E, Roussin R, could correct the immune regulation defects of T cells in MG. Altogether, our data Eymard B, Le Panse R and Berrih-Aknin S (2020) Comparative suggest that the severe defect of thymic Treg is at least partially due to MG TECs Analysis of Thymic and Blood Treg that overproduce TSLP. The Treg defects could be corrected by replacing dysfunctional in Myasthenia Gravis: Thymic Epithelial Cells Contribute to Thymic TECs by healthy TECs. These findings highlight the role of the tissue environment on the Immunoregulatory Defects. immune regulation. Front. Immunol. 11:782. doi: 10.3389/fimmu.2020.00782 Keywords: myasthenia gravis, thymus, PBMC, thymic epithelial cells, Treg, CD31, TSLP, immune regulation Frontiers in Immunology | www.frontiersin.org 1 May 2020 | Volume 11 | Article 782 fimmu-11-00782 May 4, 2020 Time: 19:41 # 2 Truffault et al. Implication of mTECS in Myasthenia Gravis INTRODUCTION distinct subpopulations: CD45RA + FoxP3lo resting Treg (rTreg) and CD45RA-FoxP3hi effector Treg (eTreg) that are both Myasthenia gravis (MG) is a chronic autoimmune disorder suppressive in vitro, while cytokine-secreting CD45RA-FoxP3lo caused, in most patients, by anti-acetylcholine receptors (AChR) cells (Fraction III, FIII) are non-suppressive (24). Finally, the antibodies, which mainly destroy AChR at the neuromuscular co-expression of chemokine receptors in Treg identifies specific junction, leading to muscle weakness and fatigability (1). functional subsets. Treg expressing chemokine receptors travel Accumulating arguments strongly support that the thymus plays to the sites of inflammation to deliver a suppressive activity. a role in the pathology of MG (2). Indeed, thymectomy has As an example, CD4 + FoxP3 + CXCR5 + cells defined as favorable clinical effects, especially in young patients (3). In follicular regulatory T cells control follicular effector T cells addition, functional and morphological abnormalities of the (CXCR5 + FoxP3neg) in lymphoid follicles (25). thymus occur very frequently in MG patients: about 50% of them In order to better understand the specific role of the present thymus hyperplasia with the development of lymphoid thymus in MG, we compared peripheral and thymic Tconv follicles, and 10 to 15% have an epithelial tumor of the thymus and Treg from controls and MG patients by combinations of (4). Thymic hyperplasia is particularly common in young women markers, and we addressed whether TECs from control and with a high level of anti-AChR antibodies (5), that decreases MG patients had distinct immune imprinting properties. We after thymectomy in association with clinical improvement showed that the phenotypic and functional defects in MG (6). Thus the thymus seems to play a key role in anti-AChR were more pronounced in the thymus than in the periphery antibody production. and that TECs from MG patients induced immune regulation Several signs of activation and inflammation can be found in defects in control CD4 + T cells, thus demonstrating that the hyperplastic thymus of MG patients. B cells spontaneously mTECs in MG patients contribute to the immunoregulatory produce anti-AChR antibodies (7), and CD4 + T cells defects in MG. express higher levels of Fas/CD95 (8) and proliferate more in response to recombinant interleukin (IL)-2 than CD4 + T cells from control individuals (9). In addition, suppression MATERIALS AND METHODS by CD4 + CD25 + thymic regulatory T cells (Treg) is severely reduced in MG patients compared with controls (10), Thymuses and Blood Samples and CD4 + CD25- thymic conventional cells (Tconv) exhibit Thymuses were obtained from MG patients (12–41 year-old) resistance to the suppressive activity (11). Taken together, these undergoing thymectomy at the “Hôpital Marie Lannelongue” or findings suggest that the thymus is chronically activated in MG. “Centre Hospitalier Universitaire de Strasbourg.” The clinical Using microarray experiments, we showed that type I- and details of the 44 patients included in the study are described in type II-interferon (IFN)-regulated genes are highly expressed in Table 1. Normal thymuses were obtained from infants (4 days to MG thymus in comparison with control thymus (12). Although 11 years) and adults (13–35 years) undergoing cardiac surgery at the origin of the thymic inflammation is still unclear, we the “Hôpital Marie Lannelongue.” showed that molecules mimicking a viral infection increase Thymocytes were isolated from thymuses by mechanical the expression of the autoantigen (AChR) as well as that of dissociation of fresh thymic tissue, as previously described (26). chemokines (13) through the production of IFN-b that appears to play a central role in MG thymic changes (14). Despite evidence of a dysregulated immune response in the TABLE 1 | Clinical characteristics of MG patients included in the study. thymus of MG patients, the role of thymic epithelial cells (TECs) has been only scarcely considered. It was shown that TECs from Age (median) 29 years MG patients overproduce IL-1, IL-6, and RANTES in comparison Sex 39 (89%) Female with TECs from healthy subjects (9, 15). Recently, we showed that 5 (11%) Male the overproduction of IL-17 in MG thymuses is sustained by a Antibody status 40 (91) Anti-AChR positive higher secretion of IL-23 by
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