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This Thesis Has Been Submitted in Fulfilment of the Requirements for a Postgraduate Degree (E.G This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Characteristics of induced regulatory T cells and bystander suppression Ben C Reynolds A thesis submitted for the degree of Doctor of Philosophy The University of Edinburgh 2012 Declaration I declare that this thesis has been written by myself, describes my own work and that this work has not been submitted for any other higher degree. Richard O’Connor performed cytokine bead arrays. Experiments in allergic airways inflammation were performed in collaboration with Karen Mackenzie and Dominika Nowakowska. Ben C Reynolds October 2012 i Acknowledgements First and foremost, thanks must go to Neil and Richard, both for the initial introduction that first sparked my interest in nephrology, and then continuing encouragement and support when I decided to sample the world of academia and research. All members of the Anderton lab have been invaluable in providing support, advice, and somebody to moan at. Many thanks to Dom for letting me use her office, to Cambers for making me appear relatively more sane, to Rhoanne for keeping me on the (almost) scientific straight and narrow, to Steph for pontoffles and cakes I will not even attempt to spell, to Hayley for a baby monkey, to Jimbo for Team B/C discussions, to Mel and Rich OC for guidance and wisdom! Particular thanks to Karen for sharing the stresses of being a paediatrician in a research environment, and to Rich Mellanby for the many hours of solidarity, when trapped in a TC hood, during the darkest hours of night. The plaque will persist long after my role as Rich’s supervisor has faded into digital obscurity. Thanks to all those who have provided technical assistance, sometimes great, sometimes small but always appreciated – Lauren, Yu, Shona, Fiona, the staff at BRR, Spike. Thanks also to the previous members of the lab; Cat, Bettina, Arjuna, who all contributed to the enjoyment of the last three years. I am grateful to all members of both Edinburgh Jitsu, and Edinburgh Jitsu Youth, for so willingly providing their bodies for me to throw around and generally alleviate my work- related stresses. Without you, I would have caused lots more damage! Thanks to my family for understanding the far too infrequent visits. Huge thanks to Gavin, for ensuring my continued survival, physically and emotionally, particularly during the less fun times. Finally, a simple thanks doesn’t really convey the extent of gratitude needed for ‘the boss’. Without the guidance, good-humoured support, and door that was always open (even when he may have wished it wasn’t), I am certain there would be no thesis to provide acknowledgements for. Whilst the dietary restrictions and some of the mental images I could probably have lived without, I consider myself honoured to have experience his tutelage, wisdom, and friendship. So cheers, Steve! ii Abstract Regulatory T cells expressing the transcription factor Foxp3 have a critical role in the maintenance of tolerance to both self and innocuous exogenous antigens. Humans and mice die from overwhelming autoimmunity in the absence of Foxp3+ Treg whilst administration of regulatory T cells has shown promise therapeutically in ameliorating autoimmunity in several animal models. Regulatory T cells arise naturally in the thymus (nTreg) but may also be induced from naïve Foxp3- cells in the presence of TGF-β (iTreg), both in vitro and in vivo. This thesis focuses on in vitro generated mouse iTreg, testing the hypothesis that they are able to effect bystander suppression; iTreg activated by a given antigen are able to suppress other responding cells with different antigen reactivities. Chapter 3 details an in vitro assay system using iTreg and responder cells recognising different antigens (TCR transgenic cells). Evidence for bystander suppression is presented and that did not require the presence of iTreg-relevant antigen but did require iTreg-relevant MHC Class II. The kinetics of iTreg suppression are discussed, with evidence presented that iTreg exert their effects early in co-culture. Chapter 4 identifies the production of three pro- inflammatory cytokines by iTreg - IFN-γ, GM-CSF, and TNF. These were not involved in the in vitro suppressive mechanism, but early abrogation of TGF-β signalling did inhibit suppression. Chapter 5 describes the in vivo function of iTreg under various experimental protocols. iTreg did not limit initial proliferation of naïve T cells in response to antigen but did limit the development of effector cells producing pro-inflammatory cytokines. Exposure to a pro-inflammatory environment in vivo led to iTreg producing IFN-γ and TNF, but not GM-CSF. This could be replicated in vitro by exposure to IL-6, IL-12 or IL-27. Finally, evidence for bystander suppression by iTreg in vivo is presented, with a reduction in effector cells producing pro-inflammatory cytokines shown in an allergic airways diease model. iii Table of Contents Declaration…………………………………………………………...…………….i Acknowledgements……………….…………………………..……….………...ii Abstract……………………………….………………..……………….…………iii Table of Contents…………………………………………………….…..……....iv List of Figures……………………………………………………………........…xii List of Tables………………………………………………………….…………xiv List of Abbreviations………………………………………………....…………xv 1 Introduction………………………………………………………………….1 1.1 General Introduction………………………………………………………...1 1.2 T cell biology………………………………………………………………..3 1.2.1 The T cell receptor……………………………………………………..3 1.2.1.1 CD4 and CD8…………………………………………………….4 1.2.2 The Major Histocompatibility Complex (MHC)………………………4 1.2.2.1 MHC structure and expression…………………………………...4 1.2.2.2 Regulation of MHC class II expression……………………….…5 1.2.2.3 Altered peptide ligands…………………………………………..5 1.2.3 Antigen processing and presentation by MHC………………………...6 1.2.4 T cell signaling………………………………….……………………...8 1.2.4.1 Signal 1…………………………………………………………...8 1.2.4.2 Signal 2…………………………………………………………...9 1.2.4.2.1 Co-stimulatory molecules…………………………………...9 1.2.4.2.2 Co-inhibitory molecules…………………………………...10 1.3 CD4+ effector subsets………………………………………………………11 1.3.1 Th1 cells………………………………………………………………11 1.3.2 Th2 cells………………………………………………………………12 1.3.3 Th17 cells……………………………………………………………..13 1.3.4 Other effector T cell subsets………………………………………….14 1.3.4.1 Th9 cells………………………………………………………...14 1.3.4.2 Th22 cells……………………………………………………….14 1.4 Cytokines…………………………………………………………………..15 1.4.1 IFN-γ………………………………………………………………….15 iv 1.4.2 ‘Th2’-associated cytokines – IL-4, IL-5, IL-13………………………17 1.4.3 IL-10…………………………………………………………………..18 1.4.4 IL-17…………………………………………………………………..20 1.4.5 TGF-β…………………………………………………………………21 1.4.6 TNF………………………………………………………………...…23 1.4.7 GM-CSF………………………………………………………………25 1.5 Effector T cell plasticity……………………………………………………26 1.6 Central tolerance…………………………………………………………...27 1.7 Peripheral tolerance………………………………………………………..29 1.7.1 Cell death……………………………………………………………..29 1.7.1.1 Active cell death………………………………………………...29 1.7.1.2 Death by neglect………………………………………………...31 1.7.2 Anergy and adaptive tolerance………………………………………..33 1.7.3 Regulation…………………………………………………………….34 1.7.3.1 Tr1 cells…………………………………………………………35 1.7.3.2 Th3 cells………………………………………………………...35 1.7.3.3 CD8+ regulatory T cells…………………………………………36 1.7.3.4 Regulatory B cells and miscellaneous…………………………..36 1.8 Loss of tolerance…………………………………………………………...36 1.8.1 Goodpasture’s disease………………………………………………...37 1.8.1.1 History and clinical presentation………………………………..37 1.8.1.2 Loss of tolerance in Goodpasture’s……………………………..38 1.8.2 EAE as a model of autoimmunity…………………………………….39 1.9 Treatment of autoimmunity………………………………………………..40 1.9.1 Corticosteroids………………………………………………………..40 1.9.2 Chemotherapy agents…………………………………………………41 1.9.3 OKT3 and derivatives………………………………………………...42 1.9.4 Alemtuzumab…………………………………………………………42 1.9.5 CTLA-4 and abatacept………………………………………………..43 1.9.6 Lymphocyte trafficking manipulation………………………………...43 1.9.7 TNF blockade…………………………………………………………44 1.9.8 Antigen-specific therapy……………………………………………...44 1.9.8.1 Peptide therapy………………………………………………….44 1.9.8.2 Other antigen-specific therapies………………………………...45 1.10 Foxp3+ regulatory T cells…………………………………………………..46 v 1.10.1 Natural Treg…………………………………………………………..46 1.10.2 Induced Treg………………………………………………………….47 1.10.3 Suppression by Treg…………………………………………………..48 1.10.4 Therapeutic application of Treg………………………………………51 1.10.4.1 Diabetes mellitus………………………………………………..52 1.10.4.2 Graft versus host disease………………………………………..52 1.10.4.3 Therapeutic hurdles……………………………………………..53 1.10.4.3.1 Identifying ‘pure’ Treg…………………………………….53 1.10.4.3.2 Plasticity of Treg…………………………………………..54 1.11 Hypothesis and aims……………………………………………………….55 2 Materials and Methods…………………………………………………...56 2.1 Mice………………………………………………………………………..56 2.2 Peptides…………………………………………………………………….56
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