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La nature des cellules dendritiques (DC) engagées lors d'une vaccination conditionne la qualité de la réponse immunitaire adaptative. L'immunisation par la peau est particulièrement efficace car elle cible de nombreuses sous-populations de DC cutanées telles que les cellules de Langerhans (LC). Cependant, les relations entre ces DC et les cellules effectrices associées à la réponse humorale ne sont pas connues. L'objectif de ma thèse est d'identifier les mécanismes cellulaires précoces impliqués dans l'initiation de la réponse humorale, dans un contexte de vaccination intradermique (i.d.) avec un antigène particulaire. En étudiant la distribution spatiale et temporelle des particules synthétiques de PLA adsorbées par la protéine p24 du VIH, nous avons observé leur prise en charge par les DC cutanées mais également par les DC résidentes des ganglions drainant de la peau. Cependant, l'étude de la réponse immunitaire a démontré que seules les cellules cutanées, et en particulier les LC, induisent la polarisation des lymphocytes T CD4+ folliculaires (TFH) et le développement des lymphocytes B sécrétant des IgA. L'immunisation i.d. a également généré l'infiltration de cellules inflammatoires au niveau du site d'injection et du ganglion. En utilisant un modèle murin Ccr2-/-, nous avons démontré que les cellules dépendantes de CCR2+ interfèrent avec la formation des TFH. Enfin, l'étude du micro-environnement ganglionnaire suggère que TNF est favorable à la polarisation des TFH. En conclusion, ces résultats soulignent l'importance de cibler les DC cutanées lors de la vaccination afin de proposer de nouvelles stratégies vaccinales. / The quality of the adaptive immune response to a vaccine is driven by the nature of dendritic cells (DCs) engaged during vaccination. Skin immunization is particularly efficient as it targets the numerous cutaneous DCs, including Langerhans cells (LCs). However, the relationship between DCs and effector cells associated with humoral immunity has not been elucidated. The main objective of my thesis was to identify cellular mechanisms implicated in the initialization of the humoral immune response, in the context of intradermal (i.d.) vaccination with particle-based antigens. In examining the spatial and temporal distribution of synthetic PLA particles adsorbed with the HIV-p24 protein, we observed their uptake by both cutaneous DCs and also skin-draining lymph node (dLNs) resident DCs. However, our immune response study highlighted that only skin cells, and in particular LCs, were able to stimulate polarization of follicular helper T cells (TFH) and the development of IgA-secreting B lymphocytes. I.d. vaccination also induced an inflammatory cell infiltration at both the injection site and in dLNs. Using a Ccr2-/- mouse model, we have shown the CCR2+ dependant cells can interfere in TFH polarization. Finally, the study of the dLN micro-environment suggested TNF can promote TFH formation. In conclusion, these findings highlight the importance of targeting skin DC in vaccination to propose new vaccine strategies.

Helper T cells (Th) are a vital component of the immune system responsible for directing other immune cells to eliminate pathogens and cancer. Specifically, Th cells facilitate B cell and cytotoxic T cell (Tc) activation and recruitment and enhance their function against cancer and infectious diseases. Th cells are a valuable resource for improving Tc responses in cancer treatment and have become a focus of immunotherapeutic research. While it is increasingly clear that helper T cells serve an important role, the details about which entities produce an effective Th cell response remain unclear. CD5 is a T cell co-receptor that negatively regulates T cell activation and helps fine-tune the TCR repertoire by altering TCR signaling during the selection process in the thymus. This work discusses the role of the co-receptor CD5 in influencing Th cell metabolism, as well as the study of two T cells called LLO118 and LLO56 that have different CD5 expression levels, and their functional response to altered peptides. Antibodies have revolutionized the world of cancer research and accelerated the development of therapies that trigger the immune system to target disease. In recent years, many antibody-based immunotherapies have emerged as effective candidates for combating cancer due to their refined specificity and ability to target a variety of epitopes. However, many therapies, such as those that target CD19 on B cell cancers, are also present on healthy cells, destroying both cancerous and healthy cells alike. Thymidine kinase 1 (TK1) is an enzyme involved in the DNA salvage pathway that converts thymidine into the nucleotide thymine. Recently, TK1 has been shown to be overexpressed on the surface of many cancers such as acute lymphoblastic leukemia. Importantly, TK1 is not expressed on the surface of healthy cells, making it an ideal cancer-specific antigen that can be targeted for cancer treatment. This work discusses our efforts to characterize TK1-specific single-chain antibodies from a yeast display library. According to the World Health Organization, genomics is defined as the study of all genes and their related functions. In contrast to genetics, genomics analyzes the entire DNA makeup of an organism rather than a single gene. In the past 20 years, the cost of genomic sequencing has decreased dramatically, making it affordable and accessible. A key area that must be addressed with genomic testing involves education about their promise, challenges, potential consequences, and ethical considerations. Genomic testing provides a powerful opportunity to educate everyone on scientific and ethical issues to increase understanding on the subject. This work discusses the influence of personal genomics in society and focuses on the importance, benefits, and consequences of genomics education in the classroom, clinic, and the public.

Des études récentes ont montré une implication de la neuropiline 1 (Nrp1)dans le contrôle de l’activation des lymphocytes T. Son invalidation s’accompagne d’une aggravation de l’encéphalite auto-immune expérimentale (EAE). La sémaphorine 3A (Sema-3A), ligand principal de la Nrp1, semble participer à une boucle autocrine de rétro contrôle négatif de la prolifération des lymphocytes T.Cependant, peu d’études ont été réalisées chez l’homme pour déterminer dans quelle(s) situation(s) la Nrp1 est exprimée par les lymphocytes T. Notre travail aconsisté à étudier l’expression de la Nrp1 par les populations lymphocytaires T humaines afin de comprendre à quel niveau peut avoir lieu ce rétro contrôle. Nous montrons que les lymphocytes T régulateurs (Treg) chez l’homme n’expriment pas laNrp1, contrairement aux Treg murins. En revanche, la Nrp1 est exprimée par les lymphocytes T effecteurs après engagement avec l’antigène, soit au niveau des organes lymphoïdes secondaires pour les lymphocytes T folliculaires helper (Tfh) en interaction avec les lymphocytes B, soit au niveau des sites d’inflammations périphériques pour les lymphocytes T effecteurs mémoires (TEM). Dans les deux cas, cette expression survient en fin d’activation et pourrait servir de frein à une activation incontrôlée des lymphocytes T.D’autre part, nous avons abordé le rôle du récepteur alpha à l’IL-2 (CD25)dans l’homéostasie des lymphocytes T. L’étude chez la souris il2ra-/- a révélé un rôle important du CD25 pour la survie des Treg in vivo, mais aussi pour l’acquisition de lymphocytes T mémoires. Seulement deux cas de déficience en CD25, associés à des maladies auto-immunes, ont été décrits chez l’homme. Cependant, ces études n’ont pas abordé à quel niveau le CD25 intervient sur l’homéostasie des lymphocytes T. Nous complétons ces études par la présentation de trois nouveaux cas de déficience en CD25 développant des maladies auto-immunes de type IPEX. Nous montrons que le CD25 intervient activement dans le maintien des populations Treg naïves et effectrices, mais aussi dans celui des populations lymphocytaires effectrices mémoires. / Recent studies have shown the involvement of neuropilin 1 (Nrp1) in the control of T cell activation, and disruption of this receptor promotes aggravation of experimental autoimmune encephalitis (EAE). Through its principal ligand,semaphorin 3A (Sema-3A), Nrp1 appears to participate in an autocrine negative feedback of T cell proliferation. However, few studies have been conducted inhumans to determine when Nrp1 is expressed by T cells. Here we show that regulatory T cells (Treg) in humans do not express Nrp1, unlike murine Treg cells. In contrast, we show that Nrp1 is expressed by effector T cells after engagement with antigen, either in secondary lymphoid organs for follicular helper T cells (Tfh) interacting with B cells, either in peripheral inflammation for effector memory T cells(TEM). We conclude that this expression corresponds to a level of late activation in both cases and may control T cell activation.The study in mice il2ra-/- revealed a significant role of IL-2 receptor alpha(CD25) for the survival of Treg in vivo, but also for the differentiation of memory T cells. Only two cases of CD25 deficiency associated with autoimmune diseases have been described in humans. However, these studies do not assess at what levelCD25 is involved in T cell homeostasis. Here we provide further insight of these studies by presenting three new cases of CD25 deficiency developing autoimmune diseases like IPEX. We show that CD25 plays an active role to maintain naive and effector Treg cell populations of, and effector memory T cell populations.

Le respect de l’équilibre entre lymphocytes T effecteurs auto-réactifs et lymphocytes T régulateurs (LTreg) est primordial dans le maintien de la tolérance aux antigènes du soi. Les partenaires cellulaires et les mécanismes moléculaires impliqués dans la rupture de l’équilibre de cette balance ne sont pas ou peu connus dans les maladies auto-immunes. Ainsi, les travaux décrits dans cette thèse portent sur le dérèglement de la balance T effecteurs/ Treg dans deux modèles de maladies auto-immunes chez l’homme: le lupus érythémateux systémique et l’anémie hémolytique auto-immune (AHAI). Nous montrons une augmentation de l’expression de la molécule de costimulation OX40L (CD252, TNFSF4) à la surface des cellules présentatrices d’antigène circulantes et infiltrant les tissus chez les patients lupiques. Cette augmentation est corrélée à l’activité de la maladie chez l’adulte comme chez l’enfant. Elle a pour conséquence l’induction de lymphocytes T effecteurs de type Tfh (T follicular helper) et le blocage des fonctions suppressives des Treg, deux acteurs majeurs dans la physiopathologie du lupus. Dans le second projet, nous montrons une augmentation de la proportion de T8reg circulants chez les patients affectés d’une AHAI à anticorps chauds en phase de rémission. Ces Treg expriment le CD25, le FoxP3 et exercent leur fonction suppressive par un mécanisme faisant intervenir l’IL10. De faibles doses d’IL-2 permettent l’expansion de cette population cellulaire in vitro. Ces résultats apportent de nouvelles connaissances dans la physiopathologie de ces deux maladies et offrent des perspectives thérapeutiques potentielles. / Respect of the balance between autoreactive T cells and regulatory T cells (LTreg) is important to maintain tolerance to self-antigens. Cellular partners and molecular mechanisms involved in the disruption of this balance are not or little known in autoimmune diseases.Thus, the work described in this thesis focuses on the disruption of the T effector/ Treg balance in two models of human autoimmune diseases: systemic lupus erythematosus and autoimmune hemolytic anemia (AIHA). We show an increased expression of the OX40L (CD252, TNFSF4) costimulatory molecule at the surface of both circulating and tissues-infiltrating antigen presenting cells in SLE patients. OX40L expression is correlated with disease activity in adults and in children and results in Tfh (follicular helper T) effector cells induction and Treg suppressive functions inhibition, two key mechanisms in the pathogenesis of lupus. In the second project, we show an increase of the circulating T8reg proportion in patients with a warm AIHA in a non-active state. These Treg express CD25, FoxP3 and exert their suppressive function by a mechanism involving IL-10. Low-dose IL-2 allows the expansion of this cell population in vitro. These results provide new insights into the pathophysiology of these diseases and offer potential therapeutic perspectives.

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Helper T cells direct the immunological response to foreign pathogens and cancer. To become activated, helper T cells must recognize unique peptides presented on major histocompatibility complex II (pMHCII) by antigen presenting cells (APCs) with their T cell receptor (TCR). While much is known about helper T cell activation signaling cascades and the subsequent roles of helper T cell subsets, the initiation of helper T cell activation by the TCR and other co-receptors is less well understood. Specifically, the affinity of the TCR for its pMHCII can change helper T cell subset fate, proliferation, and alter the risk for activation induced cell death. High affinity TCRs are attractive targets for immunotherapies, but little is known about how helper T cells respond to high affinity TCRs. Here we describe high affinity TCR activation thresholds for both full length TCRs and chimeric antigen receptor TCRs both with and without the presence of the coreceptor CD4 and propose a mechanism whereby CD4 inhibits T cell activation via Lck sequestration and a CD4-independent method. Dysregulated helper T cells play critical roles in the development and perpetuation of systemic lupus erythematosus (SLE), a systemic autoimmune disease that causes widespread inflammation and organ damage throughout the body. Chronic inflammation in SLE affects the immune response to viruses and the risk of developing cancer. However, in SLE patients, it is unclear if viruses initiate the development of cancer directly or if the effects are non-interacting and concomitant. Here we describe the interactions between SLE, viruses, and cancer risk revealing that viruses and SLE do interact to increase the both the overall cancer risk and the risk for hematological malignancies. Due to vaccine efficacy, vaccine preventable diseases (VPDs) are no longer commonly experienced or understood by the public. Vaccines are a victim of their own success and according to the World Health Organization (WHO), vaccine hesitancy (VH) is one of the top threats to global health. VH is the refusal to accept vaccinations and the reasons for VH vary across time, place, and vaccine. Refuting VH is difficult as directly confronting false assumptions can cause individuals to become more entrenched in their position resulting in confirmation bias. Adults with VH attitudes are often motivated by concerns over personal liberty, harm, independence, and body purity. Here we describe the results of a VPD interview- and education-based intervention geared towards promoting positive vaccine attitudes for young adults and demonstrate that education focused on VPDs is more effective than vaccine safety.