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Tolerogenic functions of plasmacytoid dendritic cells in T cell-medaited CNS autoimmunity

Defense Thèse de doctorat : Univ. Genève, 2016 - Sc. 4981 - 2016/09/05
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. They are characterized by their ability to secrete pro-inflammatory cytokines and large amount of type I interferon (IFN-I) upon pathogenic infections, but also express major Histocompatibility complex (MHC) and costimulatory molecules enabling them to interact with T cells. pDCs have been involved in the control of infections, but are also important actors of peripheral tolerance. The diversity of their functions, depending on the context in which they will evolve, has associated pDCs to pro-immunogenic and tolerogenic scopes. In the lab, we are principally interested in the contribution of pDCs in Multiple sclerosis, a progressive inflammatory demyelinating disease of the central nervous system (CNS). To address the role of pDCs in MS, we performed our studies in the murine model of Experimental autoimmune encephalomyelitis (EAE). Using genetically modified mice harbouring specific abrogation of Ag-presenting function in pDCs, my co-workers previously demonstrated that myelin Ag presentation by pDCs promotes the expansion of regulatory T cells (Tregs) that inhibit encephalitogenic TH1 and TH17 cell priming in secondary lymphoid organs (SLOs). In this manuscript I report our recent findings supporting that pDCs display tolerogenic functions during the priming and the effector phase of EAE development and are able to control and dampen the disease. The first study investigates the interplays between pDCs and Tregs and shows that Ag-specific MHCII interactions with Tregs licenced tolerogenic features in steady-state pDCs by inducing their expression of the indoleamine-2,3 dioxygenase (IDO1). In EAE context, Treg-educated IDO+ pDCs are required to confer suppressive functions to Tregs which promote the inhibition of encephalitogenic T cell priming in draining LNs, resulting in attenuated EAE. In the second study, we explore the therapeutic effect of pDCs transfer in EAE mice after disease onset. We show that the transfer of immature MOG35-55 pre-loaded pDCs during EAE acute phase leads to substantial reduction of CNS inflammation and significant amelioration of disease clinical scores. We demonstrate that pDC-protection relies on the massive recruitment of endogenous immature pDCs in the inflamed spinal cord via the Chemerine/CMKLR1 axis. Endogenous pDC recruitment is required to down-modulate CNS inflammation, encephalitogenic TH1 and TH17 cell responses and EAE severity. Overall this work supports previous findings showing the importance of pDCs in the regulation of CNS autoimmunity and unravel these cells for potential use, by targeting different particular functions, in the development of future therapies to treat MS patients.
Keywords Plasmacytoid dendritic cellsT cellsRegulatory T cellsAutoimmunityCentral nervous systemMultiple sclerosis
URN: urn:nbn:ch:unige-982303
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Research group Pathologie et immunologie (906)
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LIPPENS, Carla. Tolerogenic functions of plasmacytoid dendritic cells in T cell-medaited CNS autoimmunity. Université de Genève. Thèse, 2016. https://archive-ouverte.unige.ch/unige:98230

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Deposited on : 2017-10-30

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