A molecular profile of T-cell exhaustion in cancer

The first gene profiling study of cancer-specific CD8+ T-cells demonstrates that lymphocyte dysfunction in cancer tissue is due to multiple molecular alterations,1 similar as in “exhausted” T-cells in chronic infection.2 The data suggest novel drug targets, and show that T-cell exhaustion is reversible and limited to anatomical sites of disease

Particle Acceleration and Magnetic Dissipation in Relativistic Current Sheet of Pair Plasmas

We study linear and nonlinear development of relativistic and ultrarelativistic current sheets of pair plasmas with antiparallel magnetic fields. Two types of two-dimensional problems are investigated by particle-in-cell simulations. First, we present the development of relativistic magnetic reconnection, whose outflow speed is an order of the light speed c. It is demonstrated that particles are strongly accelerated in and around the reconnection region, and that most of magnetic energy is converted into "nonthermal" part of plasma kinetic energy. Second, we present another two-dimensional problem of a current sheet in a cross-field plane. In this case, the relativistic drift kink instability (RDKI) occurs. Particle acceleration also takes place, but the RDKI fast dissipates the magnetic energy into plasma heat. We discuss the mechanism of particle acceleration and the theory of the RDKI in detail. It is important that properties of these two processes are similar in the relativistic regime of T > mc^2, as long as we consider the kinetics. Comparison of the two processes indicates that magnetic dissipation by the RDKI is more favorable process in the relativistic current sheet. Therefore the striped pulsar wind scenario should be reconsidered by the RDKI.Comment: To appear in ApJ vol. 670; 60 pages, 27 figures; References and typos are fixe

Increased receptor affinity of SARS-CoV-2: a new immune escape mechanism.

‘Affinity escape’: Novel SARS-CoV-2 variants may escape immunity by raising the RBD-ACE2 affinity high enough to outcompete the avidity of neutralizing antibodies

Profile of a Serial Killer: Cellular and Molecular Approaches to Study Individual Cytotoxic T-Cells following Therapeutic Vaccination

T-cell vaccination may prevent or treat cancer and infectious diseases, but further progress is required to increase clinical efficacy. Step-by-step improvements of T-cell vaccination in phase I/II clinical studies combined with very detailed analysis of T-cell responses at the single cell level are the strategy of choice for the identification of the most promising vaccine candidates for testing in subsequent large-scale phase III clinical trials. Major aims are to fully identify the most efficient T-cells in anticancer therapy, to characterize their TCRs, and to pinpoint the mechanisms of T-cell recruitment and function in well-defined clinical situations. Here we discuss novel strategies for the assessment of human T-cell responses, revealing in part unprecedented insight into T-cell biology and novel structural principles that govern TCR-pMHC recognition. Together, the described approaches advance our knowledge of T-cell mediated-protection from human diseases

Ricci flow for homogeneous compact models of the universe

Using quaternions, we give a concise derivation of the Ricci tensor for homogeneous spaces with topology of the 3-dimensional sphere. We derive explicit and numerical solutions for the Ricci flow PDE and discuss their properties. In the collapse (or expansion) of these models, the interplay of the various components of the Ricci tensor are studied. We dedicate this paper to honor the work of Josh Goldberg.Comment: 18 pages, 2 figure

Proton acceleration in analytic reconnecting current sheets

Particle acceleration provides an important signature for the magnetic collapse that accompanies a solar flare. Most particle acceleration studies, however, invoke magnetic and electric field models that are analytically convenient rather than solutions of the governing magnetohydrodynamic equations. In this paper a self-consistent magnetic reconnection solution is employed to investigate proton orbits, energy gains, and acceleration timescales for proton acceleration in solar flares. The magnetic field configuration is derived from the analytic reconnection solution of Craig and Henton. For the physically realistic case in which magnetic pressure of the current sheet is limited at small resistivities, the model contains a single free parameter that specifies the shear of the velocity field. It is shown that in the absence of losses, the field produces particle acceleration spectra characteristic of magnetic X-points. Specifically, the energy distribution approximates a power law ~ξ-3/2 nonrelativistically, but steepens slightly at the higher energies. Using realistic values of the “effective” resistivity, we obtain energies and acceleration times that fall within the range of observational data for proton acceleration in the solar corona

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

Inhibitory Receptor Expression Depends More Dominantly on Differentiation and Activation than "Exhaustion" of Human CD8 T Cells.

Under conditions of chronic antigen stimulation, such as persistent viral infection and cancer, CD8 T cells may diminish effector function, which has been termed "exhaustion." Expression of inhibitory Receptors (iRs) is often regarded as a hallmark of "exhaustion." Here we studied the expression of eight different iRs by CD8 T cells of healthy humans, including CTLA-4, PD1, TIM3, LAG3, 2B4, BTLA, CD160, and KLRG1. We show that many iRs are expressed upon activation, and with progressive differentiation to effector cells, even in absence of long-term ("chronic") antigenic stimulation. In particular, we evaluated the direct relationship between iR expression and functionality in CD8 T cells by using anti-CD3 and anti-CD28 stimulation to stimulate all cells and differentiation subsets. We observed a striking up-regulation of certain iRs following the cytokine production wave, in agreement with the notion that iRs function as a negative feedback mechanism. Intriguingly, we found no major impairment of cytokine production in cells positive for a broad array of iRs, as previously shown for PD1 in healthy donors. Rather, the expression of the various iRs strongly correlated with T cell differentiation or activation states, or both. Furthermore, we analyzed CD8 T cells from lymph nodes (LNs) of melanoma patients. Interestingly, we found altered iR expression and lower cytokine production by T cells from metastatic LNs, but also from non-metastatic LNs, likely due to mechanisms which are not related to exhaustion. Together, our data shows that expression of iRs per se does not mark dysfunctional cells, but is rather tightly linked to activation and differentiation. This study highlights the importance of considering the status of activation and differentiation for the study and the clinical monitoring of CD8 T cells