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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

More than a year after the start of the pandemic, COVID-19 remains a global health emergency. Although the immune response against SARS-CoV-2 has been extensively studied, some points remain controversial. One is the role of antibodies in viral clearance and modulation of disease severity. While passive transfer of neutralizing antibodies protects against SARS-CoV-2 infection in animal models, titers of anti-SARS-CoV-2 antibodies have been reported to be higher in patients suffering from more severe forms of the disease. A second key question for pandemic management and vaccine design is the persistence of the humoral response. Here, we characterized the antibody response in 187 COVID-19 patients, ranging from asymptomatic individuals to patients who died from COVID-19, and including patients who recovered. We developed in-house ELISAs to measure titers of IgG, IgM and IgA directed against the RBD or N regions in patient serum or plasma, and a spike-pseudotyped neutralization assay to analyse seroneutralization. Higher titers of virus-specific antibodies were detected in patients with severe COVID-19, including deceased patients, compared to asymptomatic patients. This demonstrates that fatal infection is not associated with defective humoral response. Finally, most of recovered patients still had anti-SARS-CoV-2 IgG more than 3 months after infection.

A subset of cytokines triggers the JAK-STAT pathway to exert various functions such as the induction of inflammation and immune responses. The receptors for these cytokines are dimers/trimers of transmembrane proteins devoid of intracellular kinase activity. Instead, they rely on Janus kinases (JAKs) for signal transduction. Classical JAK-STAT signalling involves phosphorylation of cytokine receptors' intracellular tyrosines, which subsequently serve as docking sites for the recruitment and activation of STATs. However, there is evidence to show that several cytokine receptors also use a noncanonical, receptor tyrosine-independent path to induce activation of STAT proteins. We identified two main alternative modes of STAT activation. The first involves an association between a tyrosine-free region of the cytokine receptor and STATs, while the second seems to depend on a direct interaction between JAK and STAT proteins. We were able to identify the use of noncanonical mechanisms by almost a dozen cytokine receptors, suggesting they have some importance. These alternative pathways and the receptors that employ them are discussed in this review.

(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 2022

The commensal microbiota regulates susceptibility to enteric pathogens by fine-tuning mucosal innate immune responses, but how susceptibility to enteric viruses is shaped by the microbiota remains incompletely understood. Past reports have indicated that commensal bacteria may either promote or repress rotavirus replication in the small intestine of mice. We now report that rotavirus replicated more efficiently in the intestines of germ-free and antibiotic-treated mice compared to animals with an unmodified microbiota. Antibiotic treatment also facilitated rotavirus replication in type I and type III interferon (IFN) receptor-deficient mice, revealing IFN-independent proviral effects. Expression of interleukin-22 (IL-22) was strongly diminished in the intestine of antibiotic-treated mice. Treatment with exogenous IL-22 blocked rotavirus replication in microbiota-depleted wild-type and Stat1-/- mice, demonstrating that the antiviral effect of IL-22 in animals with altered microbiome is not dependent on IFN signaling. In antibiotic-treated animals, IL-22-induced a specific set of genes including Fut2, encoding fucosyl-transferase 2 that participates in the biosynthesis of fucosylated glycans which can mediate rotavirus binding. Interestingly, IL-22 also blocked rotavirus replication in antibiotic-treated Fut2-/- mice. Furthermore, IL-22 inhibited rotavirus replication in antibiotic-treated mice lacking key molecules of the necroptosis or pyroptosis pathways of programmed cell death. Taken together, our results demonstrate that IL-22 determines rotavirus susceptibility of antibiotic-treated mice, yet the IL-22-induced effector molecules conferring rotavirus resistance remain elusive.

Although sodium-glucose co-transporter 1 (SGLT1) has been identified as one of the major SGLT isoforms expressed in the heart, its exact role remains elusive. Evidences using phlorizin, the most common inhibitor of SGLTs, suggested its role in glucose transport. However, phlorizin could also affect classical facilitated diffusion via glucose transporters (GLUTs), bringing into question the relevance of SGLT1 in overall cardiac glucose uptake. Accordingly, we assessed the contribution of SGLT1 in cardiac glucose uptake using the SGLT1 knock-out mouse model, which lacks exon 1. Glucose uptake was similar in cardiomyocytes isolated from SGLT1 knock-out (KO) and control littermate (WT) mice, either under basal state, insulin, or hyperglycemia. Similarly, in vivo basal and insulin-stimulated cardiac glucose transport measured by micro-PET scan technology did not differ between WT and KO mice. Micromolar concentrations of phlorizin had no impact on glucose uptake in either isolated WT or KO-derived cardiomyocytes. However, higher concentrations (1mM) completely inhibited insulin-stimulated glucose transport without affecting insulin signaling nor GLUT4 translocation, independently from cardiomyocyte genotype. Interestingly, we discover that mouse and human hearts expressed a shorter slc5a1 transcript, leading to SGLT1 protein lacking transmembrane domains and residues involved in glucose and sodium bindings. In conclusion, cardiac SGLT1 does not contribute to overall glucose uptake, probably due to the expression of slc5a1 transcript variant. The inhibitory effect of phlorizin on cardiac glucose uptake is SGLT1-independent and can be explained by GLUT transporter inhibition. These data open new perspectives in understanding the role of SGLT1 in the heart.

Cancer immunotherapies, such as monoclonal antibodies (mAbs) directed against PD-1, aim at boosting immune responses against tumor cells. They have become a standard of care for several types of cancer. However, a majority of patients do not respond to current immunotherapies. Resistance to PD-1 blockade can in part be explained by the action of TGF-b1, an immunosuppressive cytokine activated notably by regulatory T cells (Tregs) via a mechanism that requires protein GARP. We developed antibodies against GARP:TGF-b1 complexes that block TGF-b1 activation by Tregs and we evaluated their anti-tumor efficacy in tumor-bearing mice. We observed that anti-GARP:TGF-b1 mAbs induce the regression of tumors otherwise resistant to anti-PD-1, and we showed that combined blockade of GARP:TGF-b1 and PD-1 can exert anti-tumor activity via multiple modes of action. This may prove important for the selection of cancer patients who could benefit from this novel form of immunotherapy in the clinics., (BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 2021

Allergic contact dermatitis (ACD) is an immunological reaction that develops in sensitized subjects following exposure to exogenous substances with allergenic properties. We were interested in two allergens responsible for recent ACD epidemics, methylisothiazolinone (MI), a preservative present in cosmetic and industrial products, and isobornyl acrylate (IBOA), a monomer used in plastics and glues. On the one hand, we analyzed the gradual extinction of sensitization to MI following imposed restrictions of its use. On the other hand, we studied the emergence of cases of ACD from IBOA present in blood glucose sensors and insulin pumps. We collaborated to the identification of the responsible allergens, analyzed the concomitant sensitizations with sesquiterpene lactones and discussed the distinction between irritation and allergy. We commented on the need for a revision of the legislation on medical devices., (MED - Sciences médicales) -- UCL, 2021

The transcription factor HELIOS is best known for being expressed in CD4 regulatory T cells and in murine exhausted CD8 T cells. However, data on human HELIOS+ CD8 T cells are scarce and contradictory. In blood, 21% of human CD8 T cells are HELIOS+. The two main CD8 T cell subpopulations that express HELIOS are Tc17 and Tc1 effectors that recognize viral peptides presented by HLA-E. HELIOS+ Tc1 effectors produce lower amounts of IFN-g and TNF-a compared to their HELIOS- counterparts. It remains to be understood why so many individuals maintain in their blood high amounts of Tc1 effectors that secrete low amounts of cytokines and what the connection between HELIOS and HLA-E restriction means. In ovarian carcinomas, we found TOX+ CD8 T cells that express HELIOS, suggesting the existence of either HLA-E-restricted anti-tumor CD8 T cells or two populations of exhausted T cells, namely TOX+ HELIOS- and TOX+ HELIOS+., Le facteur de transcription HELIOS est connu pour être exprimé par les lymphocytes T CD4 régulateurs et des T CD8 épuisés murins. Cependant, les données sur la nature des lymphocytes T CD8 humains HELIOS+ sont rares et contradictoires. Nous montrons ici que les lymphocytes T CD8 HELIOS+ représentent 21% des lymphocytes T CD8 du sang et contiennent deux sous-populations: des Tc17 et des Tc1 effecteurs spécifiques de peptides viraux présentés par HLA-E. Les Tc1 effecteurs HELIOS+ produisent peu d’IFN-g et de TNF-a par rapport aux HELIOS-. Il reste à comprendre pourquoi tant de Tc1 effecteurs sanguins sécrètent peu de cytokines après activation et le lien entre l’expression d’HELIOS et la restriction HLA-E. Dans des carcinomes ovariens, certains lymphocytes T CD8 TOX+ expriment HELIOS, suggérant l’existence de lymphocytes T CD8 anti-tumeur restreints par HLA-E, ou la présence de deux populations de lymphocytes T épuisés : TOX+ HELIOS- / TOX+ HELIOS+., (BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 2021