La transmission sexuelle du VIH-1 constitue le mode majeur de contamination à travers le monde. Au cours d’un rapport sexuel avec un homme séropositif vis-à-vis du VIH-1, le virus transporté par le sperme est déposé à la surface des muqueuses sous forme libre et/ou associée aux cellules mononuclées du sperme. Les particules virales peuvent alors être captées par les cellules dendritiques qui les transportent jusqu’aux lymphocytes T CD4 des ganglions lymphatiques favorisant ainsi la dissémination du virus. Plus qu’un simple véhicule, il semblerait que le plasma séminal, fraction acellulaire du sperme, puisse influencer la transmission sexuelle du VIH-1. Cependant, son rôle en tant que facilitateur ou inhibiteur de l’infection est largement débattu. La première partie de cette thèse s’intéresse à l’influence directe du plasma séminal sur la transmission sexuelle du VIH-1 via les cellules dendritiques. Nous avons montré que le TGF-β1, une des cytokines majoritaires du sperme, favorise la capture du virus par les cellules dendritiques via l’induction de l’expression de CD169, un récepteur du VIH-1 récemment décrit. Cependant, ni l’augmentation de la capture du virus ni celle de l’expression de CD169 ne sont observées lorsque les cellules sont en présence de plasma séminal. Au contraire, le fluide semble avoir tendance à diminuer la capture des particules virales et s’avère même être capable de diminuer l’induction de l’expression de CD169 par le TGF-β1 ou le LPS, suggérant un effet protecteur du plasma séminal sur la transmission sexuelle du VIH-1, même en cas de co-infection bactérienne localisée. La seconde partie de cette thèse s’intéresse à l’effet indirect du plasma séminal sur les cellules dendritiques via l’induction de la sécrétion de facteurs par les cellules épithéliales de la muqueuse, premières cellules en contact avec le fluide. A partir de deux modèles in vitro d’épithéliums simples (colorectaux et endocervicaux), les résultats obtenus montrent que les sécrétions des cellules épithéliales induites par le plasma séminal ne provoquent pas l’expression de CD169 ni la maturation des cellules dendritiques. Ces résultats contribuent à une meilleure compréhension des mécanismes précoces impliqués dans la transmission sexuelle du VIH-1 et soulignent le rôle complexe du plasma séminal dans cette dernière / Sexual transmission of Human Immunodeficiency Virus type 1 (HIV-1) remains the major way of contamination worldwide. During male to female or male transmission, the virus is deposited on the mucosal surface as cell-free or cell-associated virions carried by semen. The virions can be captured by dendritic cells (DCs) located in the mucosae. DCs play a crucial role in disseminating virus by capturing virions at the contact site and bringing them to the principal target cells in the lymph nodes i.e. the lymphocytes. More than just a carrier for viral particles, semen may also play a role in modulating HIV-1 sexual transmission. The influence of seminal plasma, the acellular fraction of semen is particularly debated. In the first part of this thesis deals with the direct influence of seminal plasma on the HIV-1 sexual transmission mediated by dendritic cells. We demonstrated that TGF-β1, a cytokine present in high concentration in seminal plasma, increases HIV-1 capture by dendritic cells through the upregulation of CD169, an HIV-1 binding molecule recently described. However, these effects are not observed when dendritic cells are incubated with seminal plasma. On the contrary, seminal plasma tends toward a decrease of HIV-1 capture by dendritic cells. Furthermore, seminal plasma is able to counteract the CD169 upregulation observed following TGF-β1 or LPS exposure indicating that seminal plasma may display a protective effect against HIV-1 transmission in the case of bacterial local coinfection. The second part of this thesis deals with the indirect effect of seminal plasma on dendritic cells through the induction of soluble factors secretion by epithelial cells, first cells in contact with the contaminated fluid. Two different epithelial cell models mimicking the female genital and intestinal tracts by using well characterized epithelial cell lines (HEC-1A and CaCo-2 respectively) have been developed. Results demonstrated that the epithelial cells secretions induced by seminal plasma do not modulate CD169 expression nor induce dendritic cells maturation. All these data contribute to a better understanding of the various mechanisms allowing HIV-1 sexual transmission and underscore the complex role of the seminal plasma in the particular case of the transmission mediated by dendritic cells

The immune system is a complex network of tissues, cells and proteins which protects us against infections and invading pathogens we encounter every day. Immunosenescence refers to age-related impairments in immune function which may contribute to increased prevalence and severity of infectious disease in the elderly. How and why ageing affects the immune system is not fully understood. Using a naturally aged mouse model, work in this thesis shows that the abundance of a rare type of lymphocyte, known as NKT cells, increased across multiple immune organs. Additionally, macrophage abundance was also altered in the lymph nodes of aged mice. Invariant NKT (iNKT) cells express an invariant T cell receptor (TCR) which recognises lipids presented on the CD1d molecule. iNKT cells can be activated and respond to invading pathogens either by recognition of antigens through TCR-CD1d interactions or cytokine-dependent means. Less is known about NKT-like cells, which also express NK cell-associated surface markers, such as CD49b, but lack an invariant TCR. Data within this thesis show that both iNKT and NKT-like cell populations are abundant in the spleen and liver of aged mice. iNKT and NKT-like cells can be divided into subpopulations based on their expression of surface markers or transcription factors, and data suggests that not all subpopulations of these cells are affected by age equally. For instance, flow cytometry showed that while spleen-derived iNKT cells are significantly increased in aged mice, within the iNKT cell population the percentage representation of CD4+ cells are significantly reduced with age. Additionally, data indicates that both iNKT and NKT-like cells from aged mice show compromised responses to in vitro stimulation compared to young controls. Using bone marrow chimeras, where either young cells are reconstituted within an aged mouse or old cells are reconstituted within a young mouse, provided the opportunity to determine whether the aged environment contributes to this diminished response. Data demonstrates that the aged environment plays at least a partial role in these age-related changes to response to stimulation, however the young environment seems unable to reverse these changes. Macrophages are phagocytes which are found within all organs of the body. Studies in this thesis show that CD169+ macrophages have diminished numbers in the lymph nodes of aged mice, but this did not seem to affect the capture of the model antigen, dextran. Further studies revealed ageing affects macrophage populations differently in the different tissues within the body. For example, macrophage numbers remain constant in the spleen with ageing, but appear to increase in density in the lungs. To conclude, ageing can cause dramatic changes to the numbers and function of different cells of the immune system across multiple organs. Furthering our understanding of the ageing immune system and the underlying mechanisms which cause age-related decline in immune function is important to design strategies to improve the quality of the lives of the elderly.