The Goldilocks Model for TCR—Too Much Attraction Might Not Be Best for Vaccine Design

Recent research on T cell-antigen interactions suggests that tighter binding is not always better at eliciting an effective immune response

Policy implementation and priorities to create healthy food environments using the Healthy Food Environment Policy Index (Food-EPI): A pooled level analysis across eleven European countries

Background: Food environments have been recognised as highly influential on population diets. Government policies have great potential to create healthy food environments to promote healthy diets. This study aimed to evaluate food environment policy implementation in European countries and identify priority actions for governments to create healthy food environments. Methods: The Healthy Food Environment Policy Index (Food-EPI) was used to evaluate the level of food environment policy and infrastructure support implementation in Estonia, Finland, Germany, Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Slovenia, and Spain in 20192021. Evidence of implementation of food environment policies was compiled in each country and validated by government officials. National experts evaluated the implementation of policies and identified priority recommendations. Findings: Finland had the highest proportion (32%, n = 7/22) of policies shaping food environments with a high level of implementation. Slovenia and Poland had the highest proportion of policies rated at very low implementation (42%, n = 10/24 and 36%, n = 9/25 respectively). Policies regarding food provision, promotion, retail, funding, monitoring, and health in all policies were identified as the most important gaps across the European countries. Experts recommended immediate action on setting standards for nutrients of concern in processed foods, improvement of school food environments, fruit and vegetable subsidies, unhealthy food and beverage taxation, and restrictions on unhealthy food marketing to children. Interpretation: Immediate implementation of policies and infrastructure support that prioritize action towards healthy food environments is urgently required to tackle the burden of obesity and diet-related non-communicable diseases in Europe. Funding: This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 774548 and from the Joint Programming Initiative A Healthy Diet for a Healthy Life. (c) 2022 The Author(s

Compressibility and thermal expansion of cubic silicon nitride

The compressibility and thermal expansion of the cubic silicon nitride (c-Si3N4) phase have been investigated by performing in situ x-ray powder-diffraction measurements using synchrotron radiation, complemented with computer simulations by means of first-principles calculations. The bulk compressibility of the c-Si3N4 phase originates from the average of both Si-N tetrahedral and octahedral compressibilities where the octahedral polyhedra are less compressible than the tetrahedral ones. The origin of the unit cell expansion is revealed to be due to the increase of the octahedral Si-N and N-N bond lengths with temperature, while the lengths for the tetrahedral Si-N and N-N bonds remain almost unchanged in the temperature range 295-1075 K

Ligand Mobility Modulates Immunological Synapse Formation and T Cell Activation

T cell receptor (TCR) engagement induces clustering and recruitment to the plasma membrane of many signaling molecules, including the protein tyrosine kinase zeta-chain associated protein of 70 kDa (ZAP70) and the adaptor SH2 domain-containing leukocyte protein of 76 kDa (SLP76). This molecular rearrangement results in formation of the immunological synapse (IS), a dynamic protein array that modulates T cell activation. The current study investigates the effects of apparent long-range ligand mobility on T cell signaling activity and IS formation. We formed stimulatory lipid bilayers on glass surfaces from binary lipid mixtures with varied composition, and characterized these surfaces with respect to diffusion coefficient and fluid connectivity. Stimulatory ligands coupled to these surfaces with similar density and orientation showed differences in their ability to activate T cells. On less mobile membranes, central supramolecular activation cluster (cSMAC) formation was delayed and the overall accumulation of CD3ζ at the IS was reduced. Analysis of signaling microcluster (MC) dynamics showed that ZAP70 MCs exhibited faster track velocity and longer trajectories as a function of increased ligand mobility, whereas movement of SLP76 MCs was relatively insensitive to this parameter. Actin retrograde flow was observed on all surfaces, but cell spreading and subsequent cytoskeletal contraction were more pronounced on mobile membranes. Finally, increased tyrosine phosphorylation and persistent elevation of intracellular Ca2+ were observed in cells stimulated on fluid membranes. These results point to ligand mobility as an important parameter in modulating T cell responses

Proteome Sampling by the HLA Class I Antigen Processing Pathway

The peptide repertoire that is presented by the set of HLA class I molecules of an individual is formed by the different players of the antigen processing pathway and the stringent binding environment of the HLA class I molecules. Peptide elution studies have shown that only a subset of the human proteome is sampled by the antigen processing machinery and represented on the cell surface. In our study, we quantified the role of each factor relevant in shaping the HLA class I peptide repertoire by combining peptide elution data, in silico predictions of antigen processing and presentation, and data on gene expression and protein abundance. Our results indicate that gene expression level, protein abundance, and rate of potential binding peptides per protein have a clear impact on sampling probability. Furthermore, once a protein is available for the antigen processing machinery in sufficient amounts, C-terminal processing efficiency and binding affinity to the HLA class I molecule determine the identity of the presented peptides. Having studied the impact of each of these factors separately, we subsequently combined all factors in a logistic regression model in order to quantify their relative impact. This model demonstrated the superiority of protein abundance over gene expression level in predicting sampling probability. Being able to discriminate between sampled and non-sampled proteins to a significant degree, our approach can potentially be used to predict the sampling probability of self proteins and of pathogen-derived proteins, which is of importance for the identification of autoimmune antigens and vaccination targets

Erythropoietin: A potent inducer of peripheral immuno/inflammatory modulation in autoimmune EAE

Background: Beneficial effects of short-term erythropoietin (EPO) theraphy have been demonstrated in several animal models of acute neurologic injury, including experimental autoimmune encephalomyelitis(EAE)-the animal model of multiple sclerosis. We have found that EPO treatment substantially reduces the acute clinical paralysis seen EAE mice and this improvements is accompanied by a large reduction in the mononuclear cell infiltration and downregulation of glial MHC class II expression within the inflamed CNS. Other reports have recently indicated that peripherally generated anti-inflammatory CD4 +Foxp3 3 regulatory T cells (Tregs) and the IL17-producing CD4+ T helper cell (Th17) subpopulations play key antagonistic roles in EAE pathogenesis. However, no information regardind the effects of EPO theraphy on the behavior of the general mononuclear-lymphocyte population, Tregs or Th17 cells in EAE has emerged. Methods and Findings: We first determined in vivo that EPO theraphy markedly suppressed MOG specific T cell proliferation and sharply reduced the number of reactive dendritic cells (CD11c positive) in EAE lumph modes during both inductive and later symptomatic phases of MOG 35-55 induced EAE. We then determined the effect in vivo of EPO on numbers of peripheral Treg cells and Th17 cells. We found that EPO treatment modulated immune balance in both the periphery and the inflamed spinal cord by promoting a large expansion in Treg cells, inhibiting Th17 polarization and abrogating proliferation of the antigen presenting dendritic cell population. Finally we utilized tissue culture assays to show that exposure to EPO in vitro similarly downregulated MOG-specific T cell proliferation and also greatly suppressed T cell production of pro-inflammatory cytokines. Conclusions: Taken together, our findings reveal an important new locus whereby EPO induces substantial long-term tissue protection in the host through signalling to several critical subsets of immune cells that reside in the peripheral lymphatic system.published_or_final_versio

Characterization of antigenic variants of hepatitis C virus in immune evasion

<p>Abstract</p> <p>Background</p> <p>Antigenic variation is an effective way by which viruses evade host immune defense leading to viral persistence. Little is known about the inhibitory mechanisms of viral variants on CD4 T cell functions.</p> <p>Results</p> <p>Using sythetic peptides of a HLA-DRB1*15-restricted CD4 epitope derived from the non-structural (NS) 3 protein of hepatitis C virus (HCV) and its antigenic variants and the peripheral blood mononuclear cells (PBMC) from six HLA-DRB1*15-positive patients chronically infected with HCV and 3 healthy subjects, the <it>in vitro </it>immune responses and the phenotypes of CD4⁺CD25⁺cells of chronic HCV infection were investigated. The variants resulting from single or double amino acid substitutions at the center of the core region of the Th1 peptide not only induce failed T cell activation but also simultaneously up-regulate inhibitory IL-10, CD25^-TGF-β⁺Th3 and CD4⁺IL-10⁺Tr1 cells. In contrast, other variants promote differentiation of CD25⁺TGF-β⁺Th3 suppressors that attenuate T cell proliferation.</p> <p>Conclusions</p> <p>Naturally occuring HCV antigenic mutants of a CD4 epitope can shift a protective peripheral Th1 immune response into an inhibitory Th3 and/or Tr1 response. The modulation of antigenic variants on CD4 response is efficient and extensive, and is likely critical in viral persistence in HCV infection.</p