title: Both Treg cells and Tconv cells are defective in the Myasthenia gravis thymus: roles of IL-17 and TNF-α.
abstract: Myasthenia gravis (MG) is an autoimmune disease in which the thymus frequently presents follicular hyperplasia and signs of inflammation and T cells display a defect in suppressive regulation. Defects in a suppressive assay can indicate either the defective function of Treg cells or the resistance of Tconv cells to suppression by Treg cells. The aim of this study was to determine which cells were responsible for this defect and to address the mechanisms involved. We first performed cross-experiment studies using purified thymic Treg cells and Tconv cells from controls (CTRL) and MG patients. We confirmed that MG Treg cells were defective in suppressing CTRL Tconv proliferation, and we demonstrated for the first time that MG Tconv cells were resistant to Treg cell suppression. The activation of MG Tconv cells triggered a lower upregulation of FoxP3 and a higher upregulation of CD4 and CD25 than CTRL cells. To investigate the factors that could explain these differences, we analyzed the transcriptomes of purified thymic Treg and Tconv cells from MG patients in comparison to CTRL cells. Many of the pathways revealed by this analysis are involved in other autoimmune diseases, and T cells from MG patients exhibit a Th1/Th17/Tfh signature. An increase in IL-17-related genes was only observed in Treg cells, while increases in IFN-γ, IL-21, and TNF-α were observed in both Treg and Tconv cells. These results were confirmed by PCR studies. In addition, the role of TNF-α in the defect in Tconv cells from MG patients was further confirmed by functional studies. Altogether, our results indicate that the immunoregulatory defects observed in MG patients are caused by both Treg cell and Tconv cell impairment and involve several pro-inflammatory cytokines, with TNF-α playing a key role in this process. The chronic inflammation present in the thymus of MG patients could provide an explanation for the escape of thymic T cells from regulation in the MG thymus.
authors.affiliation: INSERM U974, Paris, France; CNRS UMR 7215, Paris, France; UPMC Univ Paris 6, Paris, France; AIM, Institute of Myology, Paris, France. Electronic address: angeline.gradolatto@upmc.fr.
authors.forename: Angeline
authors.initials: A
authors.lastname: Gradolatto
authors.affiliation: Pasteur Institute, 25-28 Rue du Docteur Roux, 75015 Paris, France. Electronic address: dnazzal@gmail.com.
authors.forename: Dani
authors.initials: D
authors.lastname: Nazzal
authors.affiliation: INSERM U974, Paris, France; CNRS UMR 7215, Paris, France; UPMC Univ Paris 6, Paris, France; AIM, Institute of Myology, Paris, France. Electronic address: frederique.truffault@upmc.fr.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Truffault
authors.affiliation: INSERM U974, Paris, France; CNRS UMR 7215, Paris, France; UPMC Univ Paris 6, Paris, France; AIM, Institute of Myology, Paris, France. Electronic address: jacky.bismuth@upmc.fr.
authors.forename: Jacky
authors.initials: J
authors.lastname: Bismuth
authors.affiliation: Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation, Hopital Marie Lannelongue, Le Plessis-Robinson, France. Electronic address: e.fadel@ccml.fr.
authors.forename: Elie
authors.initials: E
authors.lastname: Fadel
authors.affiliation: Genopolis Consortium, University of Milano-Bicocca, Piazza della Scienza, 4, Building U4, 20126 Milan, Italy. Electronic address: maria.foti@unimib.it.
authors.forename: Maria
authors.initials: M
authors.lastname: Foti
authors.affiliation: INSERM U974, Paris, France; CNRS UMR 7215, Paris, France; UPMC Univ Paris 6, Paris, France; AIM, Institute of Myology, Paris, France. Electronic address: sonia.berrih-aknin@upmc.fr.
authors.forename: Sonia
authors.initials: S
authors.lastname: Berrih-Aknin
mesh_terms: D000293:Adolescent; D000328:Adult; D015704:CD4 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007108:Immune Tolerance; D007223:Infant; D007231:Infant, Newborn; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
chemical_list: D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018836:Inflammation Mediators; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha
keywords: Chronic inflammation; IL-17; TNF-α; Tconv cells; Thymus; Treg cells