Analysis, Isolation, and Activation of Antigen-Specific CD4 + and CD8+ T Cells by Soluble MHC-Peptide Complexes

T cells constitute the core of adaptive cellular immunity and protect higher organisms against pathogen infections and cancer. Monitoring of disease progression as well as prophylactic or therapeutic vaccines and immunotherapies call for conclusive detection, analysis, and sorting of antigen-specific T cells. This is possible by means of soluble recombinant ligands for T cells, i.e., MHC class I-peptide (pMHC I) complexes for CD8(+) T cells and MHC class II-peptide (pMHC II) complexes for CD4(+) T cells and flow cytometry. Here we review major developments in the development of pMHC staining reagents and their diverse applications and discuss perspectives of their use for basic and clinical investigations

Lower bounds for the first eigenvalue of the magnetic Laplacian

We consider a Riemannian cylinder endowed with a closed potential 1-form A and study the magnetic Laplacian with magnetic Neumann boundary conditions associated with those data. We establish a sharp lower bound for the first eigenvalue and show that the equality characterizes the situation where the metric is a product. We then look at the case of a planar domain bounded by two closed curves and obtain an explicit lower bound in terms of the geometry of the domain. We finally discuss sharpness of this last estimate.Comment: Replaces in part arXiv:1611.0193

CD8 T cell function and cross-reactivity explored by stepwise increased peptide-HLA versus TCR affinity.

Recruitment and activation of CD8 T cells occur through specific triggering of T cell receptor (TCR) by peptide-bound human leucocyte antigen (HLA) ligands. Within the generated trimeric TCR-peptide:HLA complex, the molecular binding affinities between peptide and HLA, and between TCR and peptide:HLA both impact T cell functional outcomes. However, how their individual and combined effects modulate immunogenicity and overall T cell responsiveness has not been investigated systematically. Here, we established two panels of human tumor peptide variants differing in their affinity to HLA. For precise characterization, we developed the "blue peptide assay", an upgraded cell-based approach to measure the peptide:HLA affinity. These peptide variants were then used to investigate the cross-reactivity of tumor antigen-specific CD8 T cell clonotypes derived from blood of cancer patients after vaccination with either the native or an affinity-optimized Melan-A/MART-1 epitope, or isolated from tumor infiltrated lymph nodes (TILNs). Vaccines containing the native tumor epitope generated T cells with better functionality, and superior cross-reactivity against potential low affinity escape epitopes, as compared to T cells induced by vaccines containing an HLA affinity-optimized epitope. Comparatively, Melan-A/MART-1-specific TILN cells displayed functional and cross-reactive profiles that were heterogeneous and clonotype-dependent. Finally, we took advantage of a collection of T cells expressing affinity-optimized NY-ESO-1-specific TCRs to interrogate the individual and combined impact of peptide:HLA and TCR-pHLA affinities on overall CD8 T cell responses. We found profound and distinct effects of both biophysical parameters, with additive contributions and absence of hierarchical dominance. Altogether, the biological impact of peptide:HLA and TCR-pHLA affinities on T cell responses was carefully dissected in two antigenic systems, frequently targeted in human cancer immunotherapy. Our technology and stepwise comparison open new insights into the rational design and selection of vaccine-associated tumor-specific epitopes and highlight the functional and cross-reactivity profiles that endow T cells with best tumor control capacity

Electrical probing of the spin conductance of mesoscopic cavities

We investigate spin-dependent transport in three--terminal mesoscopic cavities with spin--orbit coupling. Focusing on the inverse spin Hall effect, we show how injecting a pure spin current or a polarized current from one terminal generates additional charge current and/or voltage across the two output terminals. This allows to extract the spin conductance of the cavity from two purely electrical measurements on the output. We use random matrix theory to show that the spin conductance of chaotic ballistic cavities fluctuates universally about zero mesoscopic average and describe experimental implementations of mesoscopic spin to charge current converters.Comment: 5 Pages, 1 figure, RevTe

Vector Correlators in Lattice QCD: methods and applications

We discuss the calculation of the leading hadronic vacuum polarization in lattice QCD. Exploiting the excellent quality of the compiled experimental data for the e^+e^- --> hadrons cross-section, we predict the outcome of large-volume lattice calculations at the physical pion mass, and design computational strategies for the lattice to have an impact on important phenomenological quantities such as the leading hadronic contribution to (g-2)mu and the running of the electromagnetic coupling constant. First, the R(s) ratio can be calculated directly on the lattice in the threshold region, and we provide the formulae to do so with twisted boundary conditions. Second, the current correlator projected onto zero spatial momentum, in a Euclidean time interval where it can be calculated accurately, provides a potentially critical test of the experimental R(s) ratio in the region that is most relevant for (g-2)mu. This observation can also be turned around: the vector correlator at intermediate distances can be used to determine the lattice spacing in fm, and we make a concrete proposal in this direction. Finally, we quantify the finite-size effects on the current correlator coming from low-energy two-pion states and provide a general parametrization of the vacuum polarization on the torus.Comment: 16 pages, 9 figure files; corrected a factor 2 in Eq. (7) over the published versio

Anomalous Scale Dimensions from Timelike Braiding

Using the previously gained insight about the particle/field relation in conformal quantum field theories which required interactions to be related to the existence of particle-like states associated with fields of anomalous scaling dimensions, we set out to construct a classification theory for the spectra of anomalous dimensions. Starting from the old observations on conformal superselection sectors related to the anomalous dimensions via the phases which appear in the spectral decomposition of the center of the conformal covering group $Z(\widetilde{SO(d,2)}),$ we explore the possibility of a timelike braiding structure consistent with the timelike ordering which refines and explains the central decomposition. We regard this as a preparatory step in a new construction attempt of interacting conformal quantum field theories in D=4 spacetime dimensions. Other ideas of constructions based on the $AdS_{5}$-$CQFT_{4}$ or the perturbative SYM approach in their relation to the present idea are briefly mentioned.Comment: completely revised, updated and shortened replacement, 24 pages tcilatex, 3 latexcad figure

Vaccination with LAG-3Ig (IMP321) and Peptides Induces Specific CD4 and CD8 T-Cell Responses in Metastatic Melanoma Patients-Report of a Phase I/IIa Clinical Trial.

PURPOSE: Cancer vaccines aim to generate and maintain antitumor immune responses. We designed a phase I/IIa clinical trial to test a vaccine formulation composed of Montanide ISA-51 (Incomplete Freund's Adjuvant), LAG-3Ig (IMP321, a non-Toll like Receptor agonist with adjuvant properties), and five synthetic peptides derived from tumor-associated antigens (four short 9/10-mers targeting CD8 T-cells, and one longer 15-mer targeting CD4 T-cells). Primary endpoints were safety and T-cell responses. EXPERIMENTAL DESIGN: Sixteen metastatic melanoma patients received serial vaccinations. Up to nine injections were subcutaneously administered in three cycles, each with three vaccinations every 3 weeks, with 6 to 14 weeks interval between cycles. Blood samples were collected at baseline, 1-week after the third, sixth and ninth vaccination, and 6 months after the last vaccination. Circulating T-cells were monitored by tetramer staining directly ex vivo, and by combinatorial tetramer and cytokine staining on in vitro stimulated cells. RESULTS: Side effects were mild to moderate, comparable to vaccines with Montanide alone. Specific CD8 T-cell responses to at least one peptide formulated in the vaccine preparation were found in 13 of 16 patients. However, two of the four short peptides of the vaccine formulation did not elicit CD8 T-cell responses. Specific CD4 T-cell responses were found in all 16 patients. CONCLUSIONS: We conclude that vaccination with IMP321 is a promising and safe strategy for inducing sustained immune responses, encouraging further development for cancer vaccines as components of combination therapies. Clin Cancer Res; 22(6); 1330-40. ©2015 AACR

Limits on the Majorana neutrino mass in the 0.1 eV range

The Heidelberg-Moscow experiment gives the most stringent limit on the Majorana neutrino mass. After 24 kg yr of data with pulse shape measurements, we set a lower limit on the half-life of the neutrinoless double beta decay in 76Ge of T_1/2 > 5.7 * 10^{25} yr at 90% C.L., thus excluding an effective Majorana neutrino mass greater than 0.2 eV. This allows to set strong constraints on degenerate neutrino mass models.Comment: 6 pages (latex) including 3 postscript figures and 2 table

Limits on different Majoron decay modes of 100^{100}Mo and 82^{82}Se for neutrinoless double beta decays in the NEMO-3 experiment

The NEMO-3 tracking detector is located in the Fr\'ejus Underground Laboratory. It was designed to study double beta decay in a number of different isotopes. Presented here are the experimental half-life limits on the double beta decay process for the isotopes $^{100}$Mo and $^{82}$Se for different Majoron emission modes and limits on the effective neutrino-Majoron coupling constants. In particular, new limits on "ordinary" Majoron (spectral index 1) decay of $^{100}$Mo ($T_{1/2} > 2.7\cdot10^{22}$ y) and $^{82}$Se ($T_{1/2} > 1.5\cdot10^{22}$ y) have been obtained. Corresponding bounds on the Majoron-neutrino coupling constant are $< (0.4-1.9) \cdot 10^{-4}$ and $< (0.66-1.7) \cdot 10^{-4}$.Comment: 23 pages includind 4 figures, to be published in Nuclear Physics