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Mechanisms of Central and Peripheral T Cell Tolerance to an Antigen of the Central Nervous System

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Mechanisms of Central and Peripheral T Cell Tolerance to an Antigen of the Central Nervous System Aus dem Institut für Immunologie der Ludwig-Maximilians-Universität München Direktor: Prof. Dr. Thomas Brocker Mechanisms of central and peripheral T cell tolerance to an antigen of the central nervous system Dissertation zum Erwerb des Doktorgrades der Naturwissenschaften an der Medizinischen Fakultät der Ludwig-Maximilians-Universität München vorgelegt von Lei Wang aus Henan, China München, 2016 Mit Genehmigung der Medizinischen Fakultät der Universität München Betreuer: Prof. Dr. Ludger Klein Zweitgutachter: Priv. Doz. Dr. Klaus Dornmair Dekan: Prof. Dr. med. dent. Reinhard Hickel Tag der mündlichen Prüfung: 22.02.2017 I dedicate this work to my family. Table of Contents Summary ......................................................................................................................... 1 Zusammenfassung ........................................................................................................ 3 1. Introduction ................................................................................................................ 6 1.1 T-cell development .............................................................................................................. 6 1.1.1 Early T-cell development .............................................................................................. 6 1.1.2 T cell selection .............................................................................................................. 9 1.1.3 Antigen presenting cells in the thymus ....................................................................... 12 1.2 Central tolerance ............................................................................................................... 15 1.2.1 Clonal deletion ............................................................................................................ 17 1.2.2 Clonal diversion .......................................................................................................... 18 1.3 Peripheral tolerance .......................................................................................................... 19 1.3.1 Anergy ........................................................................................................................ 20 1.3.2 Peripheral deletion ..................................................................................................... 22 1.3.3 Ignorance ................................................................................................................... 23 1.4 Experimental Autoimmune Encephalomyelitis .................................................................. 23 1.4.1 Target autoantigen-Proteolipid protein (PLP) in EAE ................................................. 24 1.4.2 Central tolerance to PLP ............................................................................................ 25 1.5 Aim of the thesis ................................................................................................................ 28 2. Results ...................................................................................................................... 29 2.1 Lack of tolerance induction to a self-antigen in the central nervous system ..................... 29 2.1.1 Generation of a PLP174-181-specific TCR-transgenic mouse ....................................... 29 2.1.2 Analysis of T cell subsets in TCR-PLP11 mice .......................................................... 36 2.1.3 Transgenic T Cells from TCR-PLP11 Tg mice proliferate in response to PLP174-181 .. 39 2.1.4 Plp11-specific T cells can proliferate specifically in vivo ............................................ 40 2.1.5 TCR-PLP11 mice are susceptible to EAE .................................................................. 42 2.1.6 TCR-PLP11 mice lacking endogenous TCR α and β chains develop EAE spontaneously ..................................................................................................................... 43 2.1.7 Rag1-deficient TCR-PLP11 mice do not express Foxp3 ............................................ 44 2.1.8 Foxp3+ T cells presence in CD4+ T cells expressing TCR encoded by the endogenous TCR loci .......................................................................................................... 45 2.2 Mechanisms of central and peripheral T cell tolerance to an antigen of the central nervous system ....................................................................................................................... 47 I 2.2.1 Thymic development of PLP11-18-specific T cells in TCR-PLP1 mice ......................... 47 2.2.2 Contribution of thymic antigen presenting cells to tolerance induction to PLP ........... 49 2.2.3 Peripheral tolerance to PLP carried out by deletion ................................................... 52 2.2.4 ICOS and FR4 are highly expressed on TCR-PLP1 anergic CD4+ T cells ................ 54 2.2.5 Anergy is another mechanism of periphery tolerance to PLP .................................... 55 2.2.6 The presence of TCR-PLP1 PLPWT+ T cells did not hinder TCR-PLP1 PLPKO+ T cells to proliferate ................................................................................................................ 56 2.2.7 PLP expression by radioresistant cells in the periphery, but to be presented by hematopietic cells ................................................................................................................ 57 2.2.8 DCs are necessary for PLP presentation and anergy induction ................................. 59 2.2.9 Breakdown tolerance to PLP in TCR-PLP1 Tg mice lead to EAE .............................. 60 3. Discussion ................................................................................................................ 62 3.1 Lack of tolerance induction in Plp11-specific autoreactive T Cells ................................... 62 3.2 Active EAE induction in TCR-PLP11 Transgenic Mice ..................................................... 65 3.3 EAE developed spontaneously in TCR transgenic RAG-1-deficient mice ........................ 66 3.4 Central tolerance to PLP is induced by clonal deletion and concomitant Treg induction of TCR-PLP1+ T cells .............................................................................................................. 68 3.5 PLP is expressed and presented by medullary thymic epithelial cells autonomously ....... 69 3.6 Autoreactive Plp1-specific T cells are deleted or become functionally inactivation (anergy) by recognition of PLP on dendritic cells in the periphery .......................................... 73 3.7 Both central and peripheral tolerance mechanisms in maintaining tolerance to PLP ....... 76 4. Materials and Methods ............................................................................................ 77 4.1 Materials ............................................................................................................................ 77 4.1.1 Mice ............................................................................................................................ 77 4.1.2 Antibodies ................................................................................................................... 78 4.1.3 Peptides ..................................................................................................................... 79 4.1.4 Primers ....................................................................................................................... 79 4.1.5 Reagents and commercial kits ................................................................................... 81 4.1.6 Buffers and Solutions ................................................................................................. 81 4.1.7 Cell culture media ....................................................................................................... 82 4.2 Methods ............................................................................................................................ 83 4.2.1 Cell Culture ................................................................................................................. 83 4.2.2 Molecular Biology ....................................................................................................... 85 4.2.3 Immunological Methods ............................................................................................. 92 4.2.4 Animal Experiments ................................................................................................... 94 4.2.5 Statistical analysis ...................................................................................................... 97 II 5. References ................................................................................................................ 98 6. Appendix ................................................................................................................. 110 6.1 Abbreviations .................................................................................................................. 110 7. Acknowledgments ................................................................................................. 112 III Summary Myelin reactive T cells are central in the development of the autoimmune response leading to central nervous system (CNS) destruction in Multiple Sclerosis (MS) and its animal model, Experimental Autoimmune Encephalomyelitis (EAE). The underlying cellular and molecular mechanisms, however, are not fully understood. In previous
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