Acute allergic symptoms are caused by allergen-induced crosslinking of allergen-specific immunoglobulin E (IgE) bound to Fc-epsilon receptors on effector cells. Desensitization with allergen-specific immunotherapy (SIT) has been used for over a century, but the dominant protective mechanism remains unclear. One consistent observation is increased allergen-specific IgG, thought to competitively block allergen binding to IgE. Here we show that the blocking potency of the IgG response to Cat-SIT is heterogeneous. Next, using two potent, pre-selected allergen-blocking monoclonal IgG antibodies against the immunodominant cat allergen Fel d 1, we demonstrate that increasing the IgG/IgE ratio reduces the allergic response in mice and in cat-allergic patients: a single dose of blocking IgG reduces clinical symptoms in response to nasal provocation (ANCOVA, p = 0.0003), with a magnitude observed at day 8 similar to that reported with years of conventional SIT. This study suggests that simply augmenting the blocking IgG/IgE ratio may reverse allergy.
T cells expressing antigen-specific T-cell receptors (TCRs) can mediate effective tumor regression, but they often also are accompanied by autoimmune responses. To determine the TCR affinity threshold defining the optimal balance between effective antitumor activity and autoimmunity in vivo
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we used a unique self-antigen system comprising seven human melanoma gp100(209–217)-specific TCRs spanning physiological affinities (1–100 μM). We found that in vitro and in vivo T-cell responses are determined by TCR affinity, except in one case that was compensated by substantial CD8 involvement. Strikingly, we found that T-cell antitumor activity and autoimmunity are closely coupled but plateau at a defined TCR affinity of 10 µM, likely due to diminished contribution of TCR affinity to avidity above the threshold. Together, these results suggest that a relatively low-affinity threshold is necessary for the immune system to avoid self-damage, given the close relationship between antitumor activity and autoimmunity. The low threshold, in turn, indicates that adoptive T-cell therapy treatment strategies using in vitro-generated high-affinity TCRs do not necessarily improve efficacy.
High surface expression of programmed death 1 (PD-1) is associated with T-cell exhaustion; however, the relationship between PD-1 expression and T-cell dysfunction has not been delineated. We developed a model to study PD-1 signaling in primary human T cells to study how PD-1 expression affected T-cell function. By determining the number of T-cell receptor/peptide-MHC complexes needed to initiate a Ca 2+ flux, we found that PD-1 ligation dramatically shifts the dose-response curve, making T cells much less sensitive to T-cell receptor-generated signals. Importantly, other T-cell functions were differentially sensitive to PD-1 expression. We observed that high levels of PD-1 expression were required to inhibit macrophage inflammatory protein 1 beta production, lower levels were required to block cytotoxicity and IFN-γ production, and very low levels of PD-1 expression could inhibit TNF-α and IL-2 production as well as T-cell expansion. These findings provide insight into the role of PD-1 expression in enforcing T-cell exhaustion and the therapeutic potential of PD-1 blockade.
Although somatic cell reprogramming to generate inducible pluripotent stem cells (iPSCs) is associated with profound epigenetic changes, the roles and mechanisms of epigenetic factors in this process remain poorly understood. Here we identify Jmjd3 as a potent negative regulator of reprogramming. Jmjd3-deficient MEFs produced significantly more iPSC colonies than did wild-type cells, while ectopic expression of Jmjd3 markedly inhibited reprogramming. We show that the inhibitory effects of Jmjd3 are produced through both histone demethylase-dependent and -independent pathways. The latter pathway is entirely novel and involves Jmjd3 targeting of PHF20 for ubiquitination and degradation via recruitment of an E3 ligase, Trim26. Importantly, PHF20-deficient MEFs could not be converted to fully reprogrammed iPSCs, even with knockdown of Jmjd3, Ink4a or p21, indicating that this protein exerts predominant effects on reprogramming. Our findings demonstrate a previously unrecognized role of Jmjd3 in cellular reprogramming and provide molecular insight into the mechanisms by which the Jmjd3-PHF20 axis controls this process.
Background: Vitellogenin is a central regulator of honey bee life span by largely unknown mechanisms. Results: Honey bee vitellogenin has membrane affinity that is connected to cell damage recognition and antioxidant function. Conclusion: Membrane binding documents a new molecular behavior among vitellogenins. Significance: Vitellogenins are widespread phylogenetically, and their molecular behavior is essential for fitness traits in many animals.
Summary
Two-dimensional (2D) kinetic analysis directly measures molecular interactions at cell-cell junctions, thereby incorporating inherent cellular effects. By comparison, three-dimensional (3D) analysis probes the intrinsic physical chemistry of interacting molecules isolated from the cell. To understand how T-cell tumor reactivity relates to 2D and 3D binding parameters and to directly compare them, we performed kinetic analyses of a panel of human T-cell receptors (TCR) interacting with a melanoma self-antigen peptide (gp100209–217) bound to major histocompatibility complex (pMHC) in the absence and presence of coreceptor CD8. We found that while 3D parameters are inadequate to predict T-cell function, 2D parameters (which do not correlate with their 3D counterparts) show a far broader dynamic range and significantly improved correlation with T-cell function. Thus, our data support the general notion that 2D parameters of TCR–pMHC–CD8 interactions determine T-cell responsiveness and suggest a potential 2D-based strategy to screen TCRs for tumor immunotherapy.
The sequestration of Se(IV) by zero-valent iron (ZVI) is strongly influenced by the coupled effects of aging ZVI and the presence of a weak magnetic field (WMF). ZVI aged at pH 6.0 with MES as buffer between 6 and 60 h gave nearly constant rates of Se(IV) removal with WMF but with rate constants that are 10- to 100-fold greater than without. XANES analysis showed that applying WMF changes the mechanism of Se(IV) removal by ZVI aged for 6-60 h from adsorption followed by reduction to direct reduction. The strong correlation between Se(IV) removal and Fe2+ release suggests direct reduction of Se(IV) to Se(0) by Fe0, in agreement with the XANES analysis. The numerical simulation of ZVI magnetization revealed that the WMF influence on Se(IV) sequestration is associated mainly with the ferromagnetism of ZVI and the paramagnetism of Fe2+. In the presence of the WMF, the Lorentz force gives rise to convection in the solution, which narrows the diffusion layer, and the field gradient force, which tends to move paramagnetic ions (esp. Fe2+) along the higher field gradient at the ZVI particle surface, thereby inducing nonuniform depassivation and eventually localized corrosion of the ZVI surface.
We have experimentally and theoretically investigated the dependence of the intrinsic Gilbert damping parameter α0 on the spin-orbital coupling strength ξ by using L10 ordered FePd1−xPtx ternary alloy films with perpendicular magnetic anisotropy. With the time-resolved magneto-optical Kerr effect, α0 is found to increase by more than a factor of ten when x varies from 0 to 1.0. Since changes of other leading parameters are found to be neglected, the α0 has for the first time been proven to be proportional to ξ 2 .
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