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L’obésité représente un défi sanitaire global et substantiel. Engendrant de nombreuses comorbidités, son incidence augmente dans toutes les régions du monde et fait peser un poids important aussi bien sur les sociétés que les individus. Comprendre ses mécanismes et développer des stratégies thérapeutiques efficaces est donc un enjeu essentiel. A l’homéostasie, le tissu adipeux présente un environnement de type 2 anti-inflammatoire essentiel à sa fonction. La production de cytokines de type 2 (i.e. IL-5, IL-13) par les cellules lymphoïdes innées de type 2 (ILC2), et potentiellement les lymphocytes Th2, a notamment été associée au maintien de l’homéostasie par différents mécanismes impliquant l’accumulation d’éosinophiles et de macrophages anti-inflammatoires. Durant l’obésité, l’infiltrat immunitaire du tissu adipeux est profondément modifié. Les populations résidentes anti-inflammatoires deviennent alors dysfonctionnelles tandis que des cellules inflammatoires s’accumulent et mènent au développement d’une inflammation systémique chronique et de bas grade responsable des nombreuses comorbidités liées à l’obésité. De plus en plus d’études suggèrent que le maintien ou la restauration des populations anti-inflammatoires du tissu adipeux permet de limiter le développement de l’obésité et des troubles métaboliques associés. Identifier les mécanismes menant à la dysfonction des cellules anti-inflammatoires du tissu adipeux durant l’obésité présente donc un intérêt thérapeutique certain. Ce travail a ainsi permis d’identifier le rôle inattendu de deux voies de costimulation dans l’inhibition de la réponse de type 2 dans le tissu adipeux durant l’obésité. Premièrement, le récepteur costimulateur CD27, préalablement connu pour favoriser le développement de réponses lymphocytaires de type 1, a été identifié comme un régulateur négatif des Th2 du tissu adipeux, limitant à la fois leur survie et leur fonction. Ainsi, les souris CD27KO affichent un nombre de Th2 fonctionnels supé, Doctorat en Sciences, info:eu-repo/semantics/nonPublished

Most T lymphocytes, including regulatory T cells, express the CD27 costimulatory receptor in steady state conditions. There is evidence that CD27 engagement on conventional T lymphocytes favors the development of Th1 and cytotoxic responses in mice and humans, but the impact on the regulatory lineage is unknown., SCOPUS: ar.j, info:eu-repo/semantics/published

Three different signals are necessary for the activation of T cells and therefore the development of an adaptive immune response. The first signal consists on the antigen presentation by dendritic cells (DCs) in the lymphoid organs in a Major Histocompatibility Complex (MHC) context to the antigen-specific TCR. The second one, via costimulatory molecules present on the surface of APCs and T cell receptors. Signal 3 is produced by the secretion of cytokines by APCs, which signal via cytokine receptors on T cells to polarize them toward an effector phenotype.CD70 and CD27, expressed mainly on antigen presenting cells and T lymphocytes, respectively, are members of the TNF/TNFR family. The CD27/CD70 pathway has been shown to trigger the differentiation of Th1- type CD4+ T lymphocytes. Of note, the sole expression of CD70 on immature DCs have been shown to break tolerance and induce immunity, underlying the critical role of CD70 in the regulation of immune responses in vivo.It has been shown that CD27, expressed at higher levels on Tregs, is also involved in the inhibition of inflammatory responses. Indeed, in our group Dhainaut and Moser have reported that regulatory T cells control Th1 priming by selectively inhibiting the expression of CD70 by DCs in a CD27-dependent manner. Intriguingly, these observations suggest that CD27 displays opposite functions, either inducing pro-inflammatory Th1 responses (when expressed on conventional T cells (Tconvs)) or inhibiting the inflammatory responses (when expressed on Tregs). The impact of CD27 engagement on Tconvs has been widely described but remains unknown for Tregs.The objective of this project was therefore to investigate the role of CD27 inthe function and homeostasis of Tregs in vivo, as compared to Tconvs.First, we described Tregs subsets expressing or lacking-CD27, and demonstrated that Tregs expressing CD27 exhibited an activated phenotype, suggesting that CD27 could be an activator marker for Tregs. Accordingly, we, Doctorat en Sciences, info:eu-repo/semantics/nonPublished

Despite advances in targeted therapies and immunotherapy in lung cancer, chemotherapy remains the backbone of treatment in most patients at different stages of the disease. Inhaled chemotherapy is a promising strategy to target lung tumours and to limit the induced severe systemic toxicities. Cisplatin dry powder for inhalation (CIS-DPI) was tested as an innovative way to deliver cisplatin locally via the pulmonary route with minimal systemic toxicities. In vivo, CIS-DPI demonstrated a dose-dependent antiproliferative activity in the M109 orthotopic murine lung tumour model and upregulated the immune checkpoint PD-L1 on lung tumour cells. Combination of CIS-DPI with the immune checkpoint inhibitor anti-PD1 showed significantly reduced tumour size, increased the number of responders and prolonged median survival over time in comparison to the anti-PD1 monotherapy. Furthermore, the CIS-DPI and anti-PD1 combination induced an intra-tumour recruitment of conventional dendritic cells and tumour infiltrating lymphocytes, highlighting an anti-tumour immune response. This study demonstrates that combining CIS-DPI with anti-PD1 is a promising strategy to improve lung cancer therapy., SCOPUS: ar.j, info:eu-repo/semantics/published

info:eu-repo/semantics/published

Background: Yeast cells are a rich source of protein and have long been investigated for the production of yeast extract as a source of bioactive peptides with different documented bioactivity, e.g. antioxidant, ACE-inhibitory, antidiabetic, as well as prevention of chronic diseases and providing immune responces. Furthermore, yeast cells are known to contribute to generation of bioactive peptides due to their proteolytic activity during fermentation processes, and also release of antimicrobial peptides during growth. Scope and approach: Although reports on preparation and characteristic of yeast extract increased tremendously, research on the functional properties of yeast extract attributed to the content of bioactive peptides and production methods lack a systematic review. Also, the contribution of yeast cells to the production of bioactive peptides during the growth and fermentation process has not been summarized previously. This review summarizes previous studies on yeast-derived peptides, the production methods, the bioactivity, the mechanism of action, as well as the structure-function relationship, and stability of identified peptides. This article would be helpful to promote the application of yeast-derived peptides in research and commercialization. Key finding: Yeast cells and yeast extract have great potentials for producing bioactive peptides with multiple functionalities. Current scientific evidence regarding the potential health benefit of yeast highlights the need for additional investigation on the bioactivity of peptides as influenced by production and purification methods. Also, predicting and designing new peptide sequences with specific functionality with the aid of bioinformatics tools, animal and human studies will effectively transfer these findings into practical and market applications., SCOPUS: re.j, info:eu-repo/semantics/published