EPUAP classification system for pressure ulcers: European reliability study

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Single cell analysis reveals similar functional competence of dominant and nondominant CD8 T-cell clonotypes.

Immune protection from infectious diseases and cancer is mediated by individual T cells of different clonal origin. Their functions are tightly regulated but not yet fully characterized. Understanding the contribution of each T cell will improve the prediction of immune protection based on laboratory assessment of T-cell responses. Here we developed techniques for simultaneous molecular and functional assessment of single CD8 T cells directly ex vivo. We studied two groups of patients with melanoma after vaccination with two closely related tumor antigenic peptides. Vaccination induced T cells with strong memory and effector functions, as found in virtually all T cells of the first patient group, and fractions of T cells in the second group. Interestingly, high functionality was not restricted to dominant clonotypes. Rather, dominant and nondominant clonotypes acquired equal functional competence. In parallel, this was also found for EBV- and CMV-specific T cells. Thus, the nondominant clonotypes may contribute similarly to immunity as their dominant counterparts

Immunology Taught by Bacteria

It has been proposed that the innate immune system might discriminate living and virulent pathogens from dead or harmless microbes, but the molecular mechanisms by which this discrimination could occur remain unclear. Although studies of model antigens and adjuvants have illuminated important principles underlying immune responses, the specific immune responses made to living, virulent pathogens can only be discovered by studies of the living, virulent pathogens themselves. Here, I review what one particular bacterium, Legionella pneumophila, has taught us about the innate immune response. Pathogens differ greatly in the mechanisms they use to invade, replicate within, and transmit among their hosts. However, a theme that emerges is that the pathogenic activities sensed by host cells are conserved among multiple pathogenic bacteria. Thus, immunology taught by L. pneumophila may lead to a more general understanding of the host response to infection

Tests of the Equivalence Principle with Neutral Kaons

We test the Principle of Equivalence for particles and antiparticles, using CPLEAR data on tagged K0 and K0bar decays into pi^+ pi^-. For the first time, we search for possible annual, monthly and diurnal modulations of the observables |eta_{+-}| and phi_{+-}, that could be correlated with variations in astrophysical potentials. Within the accuracy of CPLEAR, the measured values of |eta_{+-}| and phi_{+-} are found not to be correlated with changes of the gravitational potential. We analyze data assuming effective scalar, vector and tensor interactions, and we conclude that the Principle of Equivalence between particles and antiparticles holds to a level of 6.5, 4.3 and 1.8 x 10^{-9}, respectively, for scalar, vector and tensor potentials originating from the Sun with a range much greater than the distance Earth-Sun. We also study energy-dependent effects that might arise from vector or tensor interactions. Finally, we compile upper limits on the gravitational coupling difference between K0 and K0bar as a function of the scalar, vector and tensor interaction range.Comment: 15 pages latex 2e, five figures, one style file (cernart.csl) incorporate

Recent NA48/2 and NA62 results

The NA48/2 Collaboration at CERN has accumulated and analysed unprecedented statistics of rare kaon decays in the $K_{e4}$ modes: $K_{e4}(+-)$ ($K^\pm \to \pi^+ \pi^- e^\pm \nu$) and $K_{e4}(00)$ ($K^\pm \to \pi^0 \pi^0 e^\pm \nu$) with nearly one percent background contamination. It leads to the improved measurement of branching fractions and detailed form factor studies. New final results from the analysis of 381 $K^\pm \to \pi^\pm \gamma \gamma$ rare decay candidates collected by the NA48/2 and NA62 experiments at CERN are presented. The results include a decay rate measurement and fits to Chiral Perturbation Theory (ChPT) description.Comment: Prepared for the Proceedings of "Moriond QCD and High Energy Interactions. March 22-29 2014." conferenc

Test of CPT Symmetry and Quantum Mechanics with Experimental data from CPLEAR

We use fits to recent published CPLEAR data on neutral kaon decays to $\pi^+\pi^-$ and $\pi e\nu$ to constrain the CPT--violation parameters appearing in a formulation of the neutral kaon system as an open quantum-mechanical system. The obtained upper limits of the CPT--violation parameters are approaching the range suggested by certain ideas concerning quantum gravity.Comment: 9 pages of uuencoded postscript (includes 3 figures

Quantitative and qualitative impairments in dendritic cell subsets of patients with ovarian or prostate cancer

Background Dendritic cells (DCs) are the most efficient antigen-presenting cells, hence initiating a potent and cancer-specific immune response. This ability (mainly using monocyte-derived DCs) has been exploited in vaccination strategies for decades with limited clinical efficacy. Another alternative would be the use of conventional DCs (cDCs) of which at least three subsets circulate in human blood: cDC1s (CD141bright), cDC2s (CD1c+) and plasmacytoid DCs. Despite their paucity, technical advances may allow for their selection and clinical use. However, many assumptions concerning the DC subset biology depend on observations from mouse models, hindering their translational potential. In this study, we characterise human DCs in patients with ovarian cancer (OvC) or prostate cancer (PrC). Patients and methods Whole blood samples from patients with OvC or PrC and healthy donors (HDs) were evaluated by flow cytometry for the phenotypic and functional characterisation of DC subsets. Results In both patient groups, the frequency of total CD141+ DCs was lower than that in HDs, but the cDC1 subset was only reduced in patients with OvC. CD141+ DCs showed a reduced response to the TLR3 agonist poly (I:C) in both groups of patients. An inverse correlation between the frequency of cDC1s and CA125, the OvC tumour burden marker, was observed. Consistently, high expression of CLEC9A in OvC tissue (The Cancer Genome Atlas data set) indicated a better overall survival. Conclusions cDC1s are reduced in patients with OvC, and CD141+ DCs are quantitatively and qualitatively impaired in patients with OvC or PrC. CD141+ DC activation may predict functional impairment. The loss of cDC1s may be a bad prognostic factor for patients with OvC

TCRep 3D: An Automated In Silico Approach to Study the Structural Properties of TCR Repertoires

TCRep 3D is an automated systematic approach for TCR-peptide-MHC class I structure prediction, based on homology and ab initio modeling. It has been considerably generalized from former studies to be applicable to large repertoires of TCR. First, the location of the complementary determining regions of the target sequences are automatically identified by a sequence alignment strategy against a database of TCR Vα and Vβ chains. A structure-based alignment ensures automated identification of CDR3 loops. The CDR are then modeled in the environment of the complex, in an ab initio approach based on a simulated annealing protocol. During this step, dihedral restraints are applied to drive the CDR1 and CDR2 loops towards their canonical conformations, described by Al-Lazikani et. al. We developed a new automated algorithm that determines additional restraints to iteratively converge towards TCR conformations making frequent hydrogen bonds with the pMHC. We demonstrated that our approach outperforms popular scoring methods (Anolea, Dope and Modeller) in predicting relevant CDR conformations. Finally, this modeling approach has been successfully applied to experimentally determined sequences of TCR that recognize the NY-ESO-1 cancer testis antigen. This analysis revealed a mechanism of selection of TCR through the presence of a single conserved amino acid in all CDR3β sequences. The important structural modifications predicted in silico and the associated dramatic loss of experimental binding affinity upon mutation of this amino acid show the good correspondence between the predicted structures and their biological activities. To our knowledge, this is the first systematic approach that was developed for large TCR repertoire structural modeling

IL-12 controls cytotoxicity of a novel subset of self-antigen-specific human CD28+ cytolytic T cells.

Activated CD8 T cells develop cytotoxicity against autologous cells bearing foreign Ags and self/tumor Ags. However, self-specific cytolysis needs to be kept under control to avoid overwhelming immunopathology. After peptide vaccination of melanoma patients, we studied molecular and functional properties of T cell subsets specific for the self/tumor Ag Melan-A/MART-1. Ex vivo analysis revealed three Ag-specific effector memory (EM) populations, as follows: CD28-negative EM (EM28(-)) T cells strongly expressing granzyme/perforin, and two EM28(+) subsets, one with high and the other with low level expression of these cytotoxic proteins. For further functional characterization, we generated 117 stable CD8 T cell clones by ex vivo flow cytometry-based sorting of these subsets. All EM28(-)-derived clones lysed target cells with high efficacy. In contrast, EM28(+)-derived clones were heterogenous, and could be classified in two groups, one with high and the other with low killing capacity, correlating with granzyme/perforin expression. High and low killer phenotypes remained surprisingly stable for several months. However, strongly increased granzyme expression and cytotoxicity were observed after exposure to IL-12. Thus, the data reveal a newly identified subset of CD28(+) conditional killer T cells. Because CD28 can mediate strong costimulatory signals, tight cytotoxicity control, as shown in this study through IL-12, may be particularly important for subsets of T cells expressing CD28

NKG2A inhibits TH2 cell effector function in vitro

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