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Newborns are highly susceptible to infections; however, the underlying mechanisms that regulate the anti-microbial T-helper cells shortly after birth remain incompletely understood. To address neonatal antigen-specific human T-cell responses against bacteria, Staphylococcus aureus (S. aureus) was used as a model pathogen and comparatively analyzed in terms of the polyclonal staphylococcal enterotoxin B (SEB) superantigen responses. Here, we report that neonatal CD4 T-cells perform activation-induced events upon S. aureus/APC-encounter including the expression of CD40L and PD-1, as well as the production of Th1 cytokines, concomitant to T-cell proliferation. The application of a multiple regression analysis revealed that the proliferation of neonatal T-helper cells was determined by sex, IL-2 receptor expression and the impact of the PD-1/PD-L1 blockade. Indeed, the treatment of S. aureus-activated neonatal T-helper cells with PD-1 and PD-L1 blocking antibodies revealed the specific regulation of the immediate neonatal T-cell responses with respect to the proliferation and frequencies of IFNγ producers, which resembled in part the response of adults’ memory T-cells. Intriguingly, the generation of multifunctional T-helper cells was regulated by the PD-1/PD-L1 axis exclusively in the neonatal CD4 T-cell lineage. Together, albeit missing memory T-cells in neonates, their unexperienced CD4 T-cells are well adapted to mount immediate and strong anti-bacterial responses that are tightly controlled by the PD-1/PD-L1 axis, thereby resembling the regulation of recalled memory T-cells of adults.

Currently, various high lift devices are being employed in the general aviation industry. The performance of these high lift devices depends on various parameters, among which the geometrical or positional parameters are one of the most important as their influence is very prominent on the aerodynamics of the wing. Hence, attention is to be given to the optimization of these devices to increase their efficiency and performance. This article focuses on the optimization of high lift devices such as leading edge slats and trailing edge flaps. The optimization is achieved with four defined configurations for each high lift device and then compared their results with each other to find the best configuration; here the best performance refers to maximization of section coefficient of lift. A two-dimensional CFD (computational Fluid Dynamics) analysis performed on best three element airfoil using SolidWorks Flow Simulation tool with variation in aerodynamic parameters as lift and pitching moment. The obtained results have an accuracy of 1.09% for maximum coefficient of lift and 0.4% for landing condition respectively. Thus the optimized NACA2412 three-element airfoil gives good aerodynamic performance.

Intercellular communication is crucial for collective regulation of cellular behaviors. While clustering T cells have been shown to mutually control the production of key communication signals, it is unclear whether they also jointly regulate their availability and degradation. Here we use newly developed reporter systems, bioinformatic analyses, protein structure modeling and genetic perturbations to assess this. We find that T cells utilize trogocytosis by competing antagonistic receptors to differentially control the abundance of immunoregulatory ligands. Specifically, ligands trogocytosed via CD28 are shuttled to the T cell surface, enabling them to co-stimulate neighboring T cells. In contrast, CTLA4-mediated trogocytosis targets ligands for degradation. Mechanistically, this fate separation is controlled by different acid-sensitivities of receptor-ligand interactions and by the receptor intracellular domains. The ability of CD28 and CTLA4 to confer different fates to trogocytosed ligands reveals an additional layer of collective regulation of cellular behaviors and promotes the robustness of population dynamics.

Topology optimization is a technique which has proven to be a very crucial and effective tool in modification of the geometry of various mechanical or load bearing components. This technique has been used in aerospace, mechanical and civil applications to save material and reduce the overall mass of the component. There are various existing topology optimization algorithms which produce remarkable results, each algorithm is unique, and the results obtained are different. Implant dentistry has become a new area where topology optimization has found a good scope. The goal of modifying a dental implant is to improve the osseointegration and enhance its stability, hence when a topological optimization study is being performed on a dental implant these additional factors are necessary to be considered. The literature pertaining to the topology optimization employed in dental implants is limited and this study focuses on the available literature and other important aspects like selection of the optimization algorithm, bone density and manufacturing method which influence the topology optimization procedure when employed in the modification of dental implants.

The monoclonal antibody against CTLA-4, Ipilimumab, is a first-in-class immune-checkpoint inhibitor approved for treatment of advanced melanoma in adults but not extensively studied in children. In light of the fact that the immune response early in life differs from that of adults, we have applied a human in vitro model stimulating CD4+ T-cells from neonates, children (1–5 years), and adults antigen-specifically with Staphylococcus aureus (S. aureus) for assessment of CTLA-4 blockade early in life. We show that T-cell proliferation as well as frequencies of antigen-specific T-cells (CD40L+CD4+) were enhanced in neonatal T-cells upon CTLA-4 blockade showing a larger variance within the group (F-test p

The blockade of inhibitory receptors such as CTLA-4 (CD152) is being used as immune-checkpoint therapy, offering a powerful strategy to restore effective immune responses against tumors. To determine signal components that are induced under the control of CTLA-4 we analyzed activated murine CD8+ T cells by quantitative proteomics. Accurate mass spectrometry revealed that CTLA-4 engagement led to central changes in the phosphorylation of proteins involved in T-cell differentiation. Beside other targets, we discovered a CTLA-4-mediated induction of the translational inhibitor programmed cell death-4 (PDCD4) as a result of FoxO1 nuclear re-localization. PDCD4 further bound a distinct set of mRNAs including Glutaminase, which points out a critical role for CTLA-4 in CD8+ T-cell metabolism. Consequently, PDCD4-deficient cytotoxic T-lymphocytes (CTLs) expressed increased amounts of otherwise repressed effector molecules and ultimately led to superior control of tumor growth in vivo. These findings reveal a novel CTLA-4-mediated pathway to attenuate CTLs and indicate the importance of post-transcriptional mechanisms in the regulation of anti-tumor immune responses.

The origin of human T-cell responses against fungal pathogens early in life is not clearly understood. Here, we show that antifungal T-cell responses are vigorously initiated within the first years of life against lysates and peptides of Candida albicans or Aspergillus fumigatus, presented by autologous monocytes. The neonatal responding T-cell pool consists of 20 different TCR-Vβ families, whereas infant and adult pools display dramatically less variability. Although we demonstrate no bias for anti-fungal IL-4 expression early in life, there was a strong bias for anti-fungal IL-17 production. Of note, only T-cells from neonates and infants show an immediate co-expression of multiple cytokines. In addition, only their T-cells co-express simultaneously transcription factors T-bet and RORγt in response to fungi and subsequently their target genes IL-17 and IFNγ. Thus, T-cells of neonates and infants are predetermined to respond quickly with high plasticity to fungal pathogens, which might give an excellent opportunity for therapeutic interventions.

Although CD8+ T cells that produce IL-17 (Tc17 cells) have been linked to host defense, Tc17 cells show reduced cytotoxic activity, which is the characteristic function of CD8+ T cells. Here, we show that CTLA-4 enhances the frequency of IL-17 in CD8+ T cells, indicating that CTLA-4 (CD152) specifically promotes Tc17 differentiation. Simultaneous stimulation of CTLA-4+/+ and CTLA-4−/− T cells in cocultures and agonistic CTLA-4 stimulation unambiguously revealed a cell-intrinsic mechanism for IL-17 control by CTLA-4. The quality of CTLA-4-induced Tc17 cells was tested in vivo, utilizing infection with the facultative intracellular bacterium Listeria monocytogenes (LM). Unlike CTLA-4+/+ Tc17 cells, CTLA-4−/− were nearly as efficient as Tc1 CTLA-4+/+ cells in LM clearance. Additionally, adoptively transferred CTLA-4−/− Tc17 cells expressed granzyme B after rechallenge, and produced Tc1 cytokines such as IFN-γ and TNF-α, which strongly correlate with bacterial clearance. CTLA-4+/+ Tc17 cells demonstrated a high-quality Tc17 differentiation program ex vivo, which was also evident in isolated IL-17-secreting Tc17 cells, with CTLA-4-mediated enhanced upregulation of Tc17-related molecules such as IL-17A, RORγt, and IRF-4. Our results show that CTLA-4 promotes Tc17 differentiation that results in robust Tc17 responses. Its inactivation might therefore represent a central therapeutic target to enhance clearance of infection.

As the blockade of inhibitory surface-molecules such as CTLA-4 on T cells has led to recent advances in antitumor immune therapy, there is great interest in identifying novel mechanisms of action of CD8+ T cells to evoke effective cytotoxic antitumor responses. Using in vitro and in vivo models, we investigated the molecular pathways underlying the CTLA-4-mediated differentiation of IL-17-producing CD8+ T cells (Tc17 cells) that strongly impairs cytotoxicity. Our studies demonstrate that Tc17 cells lacking CTLA-4 signaling have limited production of STAT3-target gene products such as IL-17, IL-21, IL-23R and RORγt. Upon re-stimulation with IL-12, these cells display fast downregulation of Tc17 hallmarks and acquire Tc1 characteristics such as IFNγ and TNF-α co-expression, which is known to correlate with tumor control. Indeed, upon adoptive transfer, these cells were highly efficient in the antigen-specific rejection of established OVA-expressing B16 melanoma in vivo. Mechanistically, in primary and re-stimulated Tc17 cells, STAT3 binding to the IL-17 promoter was strongly augmented by CTLA-4, associated with less binding of STAT5 and reduced relative activation of STAT1 which is known to block STAT3 activity. Inhibiting CTLA-4-induced STAT3 activity reverses enhancement of signature Tc17 gene products, rendering Tc17 cells susceptible to conversion to Tc1-like cells with enhanced cytotoxic potential. Thus, CTLA-4 critically shapes the characteristics of Tc17 cells by regulating relative STAT3 activation, which provides new perspectives to enhance cytotoxicity of antitumor responses.

Tc17 cells are known to express low IFN-γ and granzyme B, resulting in diminished cytotoxicity. Adoptive transfer into Ag-bearing hosts converts them partially towards IFN-γ producing phenotype retaining Tc17 characteristics like increased persistence of survival. Nevertheless molecular mechanisms involved in Tc17 lineage plasticity and stability are yet to be identified. CTLA-4, a homologue to co-stimulatory molecule CD28, diminishes cytotoxicity of Tc1 cells by selective downregulation of GranzymeB, Eomes, and IFN-γ production, but its impact on Tc17 differentiation and plasticity is not known. CTLA-4+/+ and −/− CD8+ T cells were stimulated under Tc17 conditions. Tc1 and Tc17 characteristics in these cells were analysed by flow cytometry, western blot and real-time-PCR. For plasticity studies, cells were re-stimulated and analyzed for expression of Tc17 and Tc1 characteristics. Listeria Monocytogenes(LM) infection model and B16 melanoma model were used to investigate the effects of CTLA-4 on Tc17 cell mediated clearance of infection and controlling tumor growth. CTLA-4 showcased a cell intrinsic ability to enhance Tc17 differentiation program, by sustaining the levels of IL-17 inducing factors like STAT3, RORγ T and IRF4. Adoptively transferred Tc17 cells lacking CTLA-4 signal were more effective in clearing LM infection and controlling tumor growth. Re-stimulated CTLA-4 incompetent Tc17 cells revealed that higher cytotoxicity of these cells is due to their enhanced plasticity nature to develop Tc1 characteristics. Inactivation of CTLA-4 could be a unique target for Tc17 cells, to enhance lineage plasticity and develop Tc1 characteristics with increased persistence of survival and immunity.