Th17 cells are a lineage of CD4+ T cells characterized by IL-17 secretion, which plays a crucial role in immune responses against important respiratory pathogens, such as Mycobacterium tuberculosis. In this study, we demonstrated that intranasal (i.n.) immunization leads per se to Th17-biased immune responses, regardless of the adjuvant used. The activated CD4+ T cells also showed an up-regulated expression of the chemokine receptor CCR6, which is a marker for murine Th17 cells. These results have important implications in the context of optimizing rational vaccine design, since i.n. immunization appears to be the strategy of choice for situations where the induction of a Th17 phenotype would be beneficial.
Bordetella bronchiseptica is an important pathogen causing a number of veterinary respiratory syndromes in agriculturally important and food-producing confinement-reared animals, resulting in great economic losses annually amounting to billions of euros worldwide. Currently available live vaccines are incompletely satisfactory in terms of efficacy and safety. An efficient vaccine for livestock animals would allow reducing the application of antibiotics, thereby preventing the massive release of pharmaceuticals into the environment. Here, we describe two new potential vaccine strains based on the BB7865 strain. Two independent attenuating mutations were incorporated by homologous recombination in order to make negligible the risk of recombination and subsequent reversion to the virulent phenotype. The mutations are critical for bacterial metabolism, resistance to oxidative stress, intracellular survival and in vivo persistence. The resulting double mutants BB7865 risA aroA and BB7865 risA dapE were characterized as promising vaccine candidates, which are able to confer protection against colonization of the lower respiratory tract after sublethal challenge with the wild-type strain.
In a previous study we demonstrated that intranasal (i.n.) vaccination promotes a Th17 biased immune response. Here, we show that co-administration of a pegylated derivative of α-galactosylceramide (αGCPEG) with an antigen, even in the presence of Th17-polarizing compounds, results in a strong blocking of Th17 differentiation. Additional studies demonstrated that this phenomenon is specifically dependent on soluble factors, like IL-4 and IFNγ, which are produced by NKT cells. Even NK1.1 negative NKT cells, which by themselves produce IL-17A, are able to block Th17 differentiation. It follows that the use of αGCPEG as adjuvant would enable to tailor Th17 responses, according to the specific clinical needs. This knowledge expands our understanding of the role played by NKT cells in overall control of the cytokine microenvironment, as well as in the overall shaping of adaptive immune responses.
Glucose-derived mannose is a common component of glycoproteins, and its deficiency leads to a severe defect in protein glycosylation and failure in basic cell functions. In this work, we show that mannose metabolism is essential for IFN-γ production by mouse Th1 cells. In addition, we demonstrate that the susceptibility of Th1 cells to glycolysis restriction depends on the activation conditions and that under diminished glycolytic flux, mannose availability becomes the limiting factor for IFN-γ expression. This study unravels a new role for glucose metabolism in the differentiation process of Th1 cells, providing a mechanistic explanation for the importance of glycolysis in immune cell functions.
The chemokine receptor CXCR3, which was shown to take part in many inflammatory processes, is considered as a Th1 specific marker. Here, we show in a mouse model that CXCR3 expressing CD4+ cells preferentially migrate to the peritoneal cavity under steady-state conditions. The peritoneal cavity milieu leads to an up-regulated expression of CXCR3. However, blocking of known ligands of this chemokine receptor did not alter the preferential migration. The peritoneal cavity environment also results in an increased percentage of memory cells producing cytokines. Up-regulation of IFNγ production occurs mostly in CXCR3+ cells considered as Th1, whereas the up-regulation of IL-4 affects mostly in CXCR3− cells which are considered as Th2. We conclude that the peritoneal cavity does not change the Th-lineage of the cells, but that domination of this anatomic niche by Th1 cells rather results from preferential migration to this compartment.
Asthma is a common chronic inflammatory disease. Although effective asthma therapies are available, part of asthmatic population do not respond to these treatment options. In this work we present the result of development of CPL302-253 molecule, a selective PI3Kδ inhibitor. This molecule is intended to be a preclinical candidate for dry powder inhalation in asthma treatment. Studies we performed showed that this molecule is safe and effective PI3Kδ inhibitor that can impact many immune functions. We developed a short, 15-day HDM induced asthma mouse model, in which we showed that CPL302-253 is able to block inflammatory processes leading to asthma development in vivo.
Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: α, β, γ, δ) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis. In this work, we synthesized a library of benzimidazole derivatives of pyrazolo[1,5-a]pyrimidine representing a collection of new, potent, active, and selective inhibitors of PI3Kδ, displaying IC50 values ranging from 1.892 to 0.018 μM. Among all compounds obtained, CPL302415 (6) showed the highest activity (IC50 value of 18 nM for PI3Kδ), good selectivity (for PI3Kδ relative to other PI3K isoforms: PI3Kα/δ = 79; PI3Kβ/δ = 1415; PI3Kγ/δ = 939), and promising physicochemical properties. As a lead compound synthesized on a relatively large scale, this structure is considered a potential future candidate for clinical trials in SLE treatment.
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