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Thesis Reference Thesis Modulation of peripheral T cell responses by unconventional antigen-presenting cells: role of plasmacytoid dendritic cells in anti-tumor immunity and lymphatic endothelial cells in autoimmunity HUMBERT, Marion Abstract The aim of this thesis was to characterize the role of plasmacytoid dendritic cells (pDCs) and lymphatic endothelial cells (LECs) in the modulation of peripheral T cell responses, with a particular focus on MHC class II-restricted antigen presentation. Depending on the immunological context, pDC MHCII-mediated antigen-presenting functions can be either tolerogenic or immunogenic. For instance, pDCs are maintained in a tolerogenic state by the tumor microenvironment. In the first part of this thesis, we asked the question whether tumor-associated pDCs could undergo a tolerogenic-to-immunogenic reprogramming following the intratumoral administration of CpG-B, a TLR9 ligand, along with a model MHC-II-restricted tumor antigenic peptide. LECs from lymph nodes (LN-LECs) were shown to impact peripheral CD8+ T cell responses, as antigen-presenting cells (APCs). Emerging evidence is in favor of a role for LN-LECs in CD4+ T cell tolerance to MHC-II-restricted antigens, although this phenomenon is still a matter of debate. In the second part of this thesis, we sought to determine the contribution of LN-LECs as MHC-II-restricted APCs [...] Reference HUMBERT, Marion. Modulation of peripheral T cell responses by unconventional antigen-presenting cells: role of plasmacytoid dendritic cells in anti-tumor immunity and lymphatic endothelial cells in autoimmunity. Thèse de doctorat : Univ. Genève, 2019, no. Sc. 5308 DOI : 10.13097/archive-ouverte/unige:115554 URN : urn:nbn:ch:unige-1155544 Available at: http://archive-ouverte.unige.ch/unige:115554 Disclaimer: layout of this document may differ from the published version. 1 / 1 UNIVERSITÉ DE GENÈVE Département de Biologie Cellulaire FACULTÉ DES SCIENCES Professeur Jean-Claude Martinou Département de Pathologie et Immunologie FACULTÉ DE MÉDECINE Professeure Stéphanie Hugues Modulation of peripheral T cell responses by unconventional antigen-presenting cells Role of plasmacytoid dendritic cells in anti-tumor immunity and lymphatic endothelial cells in autoimmunity THÈSE présentée à la Faculté des Sciences de l’Université de Genève pour obtenir le grade de Docteur ès Sciences, mention Biologie par Marion HUMBERT de Échirolles (France) Thèse n° 5308 Atelier d’impression ReproMail Genève 2019 À Valentina À mes parents et à mon frère « Toutes les grandes personnes ont d’abord été des enfants, mais peu d’entre elles s’en souviennent. » “All grown-ups were once children, but only few of them remember it.” Antoine de St Exupéry --- « Tout le monde est un génie. Mais si vous jugez un poisson sur ses capacités à grimper à un arbre, il passera sa vie à croire qu’il est stupide. » “Everybody is a genius. But if you judge a fish by its ability to climb a tree, it will live its whole life believing that it is stupid.” Albert Einstein (attributed to) --- « La seule voie qui offre quelque espoir d'un avenir meilleur pour toute l'humanité est celle de la coopération et du partenariat. » “The only path that provides hope for a better future for all humanity is cooperation and partnership.” Kofi Annan ABSTRACT A tightly regulated balance between immune activation and tolerance is required in order for the immune system to mount efficient immune responses without inducing adverse effects, such as autoimmunity. T cell responses, which play central roles in adaptive immunity, are modulated by antigen-presenting cells (APCs). In addition to professional APCs, several cell types have the ability to cross-present antigens via major histocompatibility complex class I (MHC-I) to CD8+ T cells and/or to present antigens through MHC-II to CD4+ T cells, as unconventional APCs, leading to various outcomes on T cell responses, depending on the context and the type of APC. The aim of this thesis was to characterize the role of plasmacytoid dendritic cells (pDCs) and lymphatic endothelial cells (LECs), in the modulation of peripheral T cell responses, as unconventional APCs, with a particular focus on MHC-II-restricted antigen presentation. Plasmacytoid DCs are professional producers of type I interferon and also possess the ability to present antigen to T cells. These cells are extremely plastic and, depending on the immunological context, their MHCII-mediated antigen-presenting functions can be either tolerogenic or immunogenic. For instance, pDCs are maintained in a tolerogenic state by the tumor microenvironment (TME). However, the power of pDCs that are not immersed in the TME can be harnessed to mount potent anti-tumor responses. In tumor-bearing mice, distal lymph node (LN) pDCs can be activated by a contralateral vaccination with the TLR9 ligand CpG-B, along with a model MHC-II-restricted tumor antigenic peptide, enhancing their MHC-II-mediated antigen-presenting functions and leading to anti-tumor immunity through Th17 cell priming. We asked the question whether tumor-associated pDCs could undergo a tolerogenic-to-immunogenic reprogramming following the intratumoral administration of the above-mentioned treatment. Although it led to tumor growth control, this local treatment did not reverse the tolerogenic phenotype of pDCs. These cells remained refractory to the treatment and therefore did not contribute to its efficacy. On the contrary, the working model we propose rather involves cooperation between neutrophils, conventional DCs and T cells that leads to tumor growth control. LECs, a subset of LN stromal cells (LNSCs), long thought to function as simple scaffolds, were recently shown to indirectly affect T cell responses in many ways. In addition, LN-LECs have the ability to directly impact peripheral T cell responses as unconventional APCs. LN-LECs present MHC-I-restricted endogenously-expressed peripheral tissue-restricted antigens (PTAs) to CD8+ T cells, inducing their elimination by clonal deletion. Emerging evidence is in v favor of a role for LNSCs in CD4+ T cell tolerance to MHC-II-restricted PTAs, although this phenomenon is still a matter of debate. We recently showed that elderly naïve mice, in which MHC-II expression was abrogated in LNSCs, presented signs of spontaneous autoimmunity. Here, I report our recent findings regarding the contribution of LECs as MHC-II-restricted APCs to autoreactive CD4+ T cell responses in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. The selective genetic ablation of MHC-II in LECs exacerbated disease severity. In contrast, the genetic enforcement of MHC-II-restricted myelin-derived peptide presentation in LECs led to delayed onset and dampened EAE severity, accompanied by a drastic decrease in the spinal cord CD4+ T cell infiltrate and a modulation of these cells towards a tolerogenic phenotype. The CD4+ T cell numbers and phenotype in the LNs draining the site of EAE immunization were unaffected, suggesting that this pathway may inhibit effector T cell responses, rather than the priming of naïve T cells in LNs. Our results highlight a role for LECs as unconventional tolerogenic APCs in EAE. Altogether, our studies highlight important contributions of unconventional APCs in shaping peripheral T cell responses. Therefore, these unusual pathways need to be considered in the development of therapies aiming at modulating immune responses in disease development. vi RÉSUMÉ Afin de générer des réponses immunitaires efficaces tout en évitant des effets secondaires tels que l’auto-immunité, un équilibre entre activation et tolérance doit être finement régulé. Les réponses médiées par les lymphocytes T, qui jouent un rôle central dans l’immunité adaptative, sont modulées par les cellules présentatrices d’antigènes (CPA). En plus des CPA professionnelles, plusieurs types de cellules ont la capacité de cross-présenter des antigènes par le complexe d’histocompatibilité majeur de classe I (CMH-I) aux lymphocytes T CD8+ et/ou de présenter des antigènes par le CMH-II aux lymphocytes T CD4+, en tant que CPA non-conventionnelles. Selon le contexte et le type de CPA, les conséquences sur les réponses lymphocytaires T sont variables. L’objectif de cette thèse était de caractériser le rôle des cellules plasmacytoïdes dendritiques (pDC) et des cellules endothéliales lymphatiques (LEC), en tant que CPA non-conventionnelles, dans la modulation des réponses lymphocytaires T périphériques, avec un intérêt particulier pour la présentation d’antigènes restreinte par les molécules du CMH-II. Les pDC sont des cellules sécrétrices d’interféron de type I professionnelles, qui ont également la capacité de présenter des antigènes aux lymphocytes T. Ces cellules ont des propriétés très plastiques et leurs fonctions de présentation d’antigènes restreinte par les molécules du CMH-II peuvent conduire à des effets tolérogènes ou immunogènes, selon le contexte. Les pDCs associées aux tumeurs (TA-pDC) sont maintenues dans un état tolérogène par le micro-environnement tumoral (MET). Cependant, le potentiel immunogène des pDC qui ne sont pas immergées dans le MET peut être optimisé afin de générer des réponses immunitaires anti- tumorales efficaces. Dans des souris porteuses de tumeurs, les pDC des ganglions lymphatiques distaux peuvent être activées par une vaccination contralatérale avec du CpG-B, un ligand du TLR9, avec un peptide dérivé d’un antigène tumoral modèle présenté par les molécules du CMH- II. Cette vaccination augmente la capacité de
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