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Thesis Reference Thesis Tolerogenic functions of plasmacytoid dendritic cells in T cell-medaited CNS autoimmunity LIPPENS, Carla Abstract T cell lymphocytes play an essential role in the adaptive immunity. They arise from the hematopoietic compartment and reach the thymus, where they achieve their development through specialized maturation and selection steps. Immune system comprises specific and complex mechanisms in the thymus and the periphery aiming at preventing the generation and the survival of self-reactive T cells that could lead to autoimmune disorders. These mechanisms are known as central and peripheral tolerance and rely on different cellular actors such as medullary thymic epithelial cells (mTECs), dendritic cells (DCs), lymph node stromal cells (LNSCs) and regulatory T and B cells. Self-reactive T cells escaping thymic central tolerance are kept in check in the periphery through specific mechanisms that include T cell anergy, T cell deletion and Treg induction. Although conventional DCs (cDCs) have been first in line in mediating peripheral tolerance, increasing evidence demonstrates the contribution of other actors such as plasmacytoid dendritic cells (pDCs) in this process. pDCs are important linkers of the innate and adaptive immunity. [...] Reference LIPPENS, Carla. Tolerogenic functions of plasmacytoid dendritic cells in T cell-medaited CNS autoimmunity. Thèse de doctorat : Univ. Genève, 2016, no. Sc. 4981 DOI : 10.13097/archive-ouverte/unige:98230 URN : urn:nbn:ch:unige-982303 Available at: http://archive-ouverte.unige.ch/unige:98230 Disclaimer: layout of this document may differ from the published version. 1 / 1 UNIVERSITE DE GENEVE Département de Biologie Cellulaire FACULTE DES SCIENCES Professeur Didier Picard Département de Pathologie et Immunologie FACULTE DE MEDECINE Professeur Stéphanie Hugues Tolerogenic functions of plasmacytoid dendritic cells in T cell-mediated CNS autoimmunity THESE présentée à la Faculté des sciences de l’Université de Genève pour obtenir le grade de Docteur ès sciences, mention biologie par Carla Lippens de Avignon (France) Thèse n°4981 Atelier d’impression ReproMail Genève 2016 1 | P a g e 2 | P a g e TABLE OF CONTENTS List of figures .............................................................................................................................. 5 Abbreviations ............................................................................................................................. 6 Abstract .................................................................................................................................... 10 Résumé en français .................................................................................................................. 11 I. Introduction ...................................................................................................................... 15 1. T cell development and immunity ................................................................................ 15 1.1. Thymic T cell selection ........................................................................................... 15 1.2. Central Tolerance: Negative selection in the thymus ............................................ 18 1.3. T cell homeostasis .................................................................................................. 22 1.4. T cell Responses ..................................................................................................... 22 2. Role of plasmacytoid dendritic cells in T cell tolerance and Autoimmunity ................. 36 2.1. pDCs: who are they? .............................................................................................. 36 2.2. Role of pDCs in T cell tolerance and autoimmunity .............................................. 45 3. CNS autoimmunity ........................................................................................................ 58 3.1. Multiple Sclerosis ................................................................................................... 59 3.2. pDC implication in MS ............................................................................................ 74 3.3. Other CNS autoimmune disorders ......................................................................... 75 4. Scientific interest of my project .................................................................................... 76 4.1. Scientific context .................................................................................................... 76 4.2. Hypotheses and Work axis ..................................................................................... 83 II. Materiel and methods / Results ....................................................................................... 86 1. Section 1 ........................................................................................................................ 86 2. Section 2 ...................................................................................................................... 129 3 | P a g e III. Discussion and Perspectives ........................................................................................ 151 IDO-orchestrated interplays between pDCs and Tregs inhibit autoreactive T cells priming in SLOs during EAE .................................................................................................................. 152 Therapeutic transfer of syngenic pDCs ameliorates EAE ................................................... 164 IV. Conclusion ................................................................................................................... 170 V. References ...................................................................................................................... 172 VI. Acknowledgements ..................................................................................................... 202 4 | P a g e LIST OF FIGURES Figure I-1 Organization of T cell development and selection in the thymus. .......................... 17 Figure I-2 Thymocyte outcome is dependent on the affinity of TCR for self-peptide-MHC complexes. ................................................................................................................................ 21 Figure I-3 Polarisation of CD4 + T cell subsets. .......................................................................... 25 Figure I-4 Direct inhibition of Foxp3 - lymphocytes by Tregs. .................................................. 32 Figure I-5 suppression of DC functions By Treg cells. .............................................................. 34 Figure I-6 Main transcription and growth factors governing pDC subset development in the Bone marrow ............................................................................................................................ 38 Figure I-7 Major markers differentiating human and mouse pDCs. ........................................ 40 Figure I-8 pDCs link Innate and adaptive immunity Through diverse Functions. .................... 45 Figure I-9 Immunopathology of Multiple sclerosis and cellular targets of current treatments. .................................................................................................................................................. 73 Figure III-1 Effects of IFN-γ and TGF-β treatments on the expression of IDO by pDcs. ......... 156 Figure III-2 IDO-dependent metabolic control of T cell and Treg responses relying on GCN2 expression .............................................................................................................................. 159 Figure III-3 IDO-orchestrated crosstalk between pDCs and Tregs inhibits CNS Autoimmunity ................................................................................................................................................ 163 Figure IV-1 Tolerogenic functions of pDCs in EAE .................................................................. 171 5 | P a g e ABBREVIATIONS AICD Activation-induced cell death AIRE Autoimmune regulator Ag Antigen APC Antigen presenting cell APECED Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy APS1 Autoimmune polyendocrinopathy syndrome 1 ATP Adenosine triphosphate BBB Blood brain barrier BBE Bickerstaff brainstem encephalitis BDCA-2 Blood dendritic cell antigen-2 BECs Blood endothelial cell BM Bone marrow BMDC Bone marrow derived dendritic cells BLB Blood-leptomeningeal barrier BST-2 Bone marrow stromal antigen-2 CCL Chemokine ligand CCR Chemokine receptor CD Cluster of differentiation cDC Conventional dendritic cell CDP Common dendritic progenitor CIS Clinical isolated syndrom CNS Central nervous system CRAMP Cathelicidin-related antimicrobial peptide CSF Cerebrospinal fluid cTECs Cortical thymic epithelial cell CTLA-4 Cytotoxic T-lymphocyte associated antigen CXCL Chemokine (C-X-C motif) ligand CXCR Chemokine (C-X-C motif) receptor 6 | P a g e DAMP Domage-associated molecular pattern DC Dendritic cell dLN Draining lymph node DMT Disease-modifying therapies DN Double negative DTR Diphteria toxin receptor EAE Experimental autoimmune encephalomyelitis EBV Epstein Barr virus eTAC Extrathymic Aire expressing cell FC Facilitating cells FRC Fibroblastic reticular cell Flt3L Fms-like tyrosine kinase 3 ligand FoxP3 Forkhead box P3 FS Fisher syndrome GA Glaterimer acetate GALT Gut associated lymphoid tissues GBS Guillain-Barré-Syndrome GCN2 General control nonderepressing 2 GM-CSF Granulocytes macrophage-colony stimulating
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