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

CpG-ODN-induced sustained expression of BTLA mediating selective inhibition of human B cells.

BTLA (B- and T-lymphocyte attenuator) is a prominent co-receptor that is structurally and functionally related to CTLA-4 and PD-1. In T cells, BTLA inhibits TCR-mediated activation. In B cells, roles and functions of BTLA are still poorly understood and have never been studied in the context of B cells activated by CpG via TLR9. In this study, we evaluated the expression of BTLA depending on activation and differentiation of human B cell subsets in peripheral blood and lymph nodes. Stimulation with CpG upregulated BTLA, but not its ligand: herpes virus entry mediator (HVEM), on B cells in vitro and sustained its expression in vivo in melanoma patients after vaccination. Upon ligation with HVEM, BTLA inhibited CpG-mediated B cell functions (proliferation, cytokine production, and upregulation of co-stimulatory molecules), which was reversed by blocking BTLA/HVEM interactions. Interestingly, chemokine secretion (IL-8 and MIP1β) was not affected by BTLA/HVEM ligation, suggesting that BTLA-mediated inhibition is selective for some but not all B cell functions. We conclude that BTLA is an important immune checkpoint for B cells, as similarly known for T cells

BAFF 60-mer, and Differential BAFF 60-mer Dissociating Activities in Human Serum, Cord Blood and Cerebrospinal Fluid.

B cell activation factor of the TNF family (BAFF/BLyS), an essential B cell survival factor of which circulating levels are elevated in several autoimmune disorders, is targeted in the clinic for the treatment of systemic lupus erythematosus (SLE). The soluble form of BAFF can exist as 3-mer, or as 60-mer that results from the ordered assembly of twenty 3-mers and that can be obtained from naturally cleaved membrane-bound BAFF or made as a recombinant protein. However, which forms of soluble BAFF exist and act in humans is unclear. In this study, BAFF 3-mer and 60-mer in biological fluids were characterized for size, activity and response to specific stimulators or inhibitors of BAFF. Human cerebrospinal fluids (CSF) from patients with multiple sclerosis and adult human sera contained exclusively BAFF 3-mer in these assays, also when BAFF concentrations were moderately SLE or highly (BAFFR-deficient individual) increased. Human sera, but not CSF, contained a high molecular weight, saturable activity that dissociated preformed recombinant BAFF 60-mer into 3-mer. This activity was lower in cord blood. Cord blood displayed BAFF levels 10-fold higher than in adults and consistently contained a fair proportion of active high molecular weight BAFF able to dissociate into 3-mer but not endowed with all properties of recombinant BAFF 60-mer. If BAFF 60-mer is produced in humans, it is dissociated, or at least attenuated in the circulation

UV-induced ligand exchange in MHC class I protein crystals

High-throughput structure determination of protein−ligand complexes is central in drug development and structural proteomics. To facilitate such high-throughput structure determination we designed an induced replacement strategy. Crystals of a protein complex bound to a photosensitive ligand are exposed to UV light, inducing the departure of the bound ligand, allowing a new ligand to soak in. We exemplify the approach for a class of protein complexes that is especially recalcitrant to high-throughput strategies: the MHC class I proteins. We developed a UV-sensitive, “conditional”, peptide ligand whose UV-induced cleavage in the crystals leads to the exchange of the low-affinity lytic fragments for full-length peptides introduced in the crystallant solution. This “in crystallo” exchange is monitored by the loss of seleno-methionine anomalous diffraction signal of the conditional peptide compared to the signal of labeled MHC β2m subunit. This method has the potential to facilitate high-throughput crystallography in various protein families

Constant regulation for stable CD8 T-cell functional avidity and its possible implications for cancer immunotherapy.

The functional avidity (FA) of cytotoxic CD8 T cells impacts strongly on their functional capabilities and correlates with protection from infection and cancer. FA depends on TCR affinity, downstream signaling strength, and TCR affinity-independent parameters of the immune synapse, such as costimulatory and inhibitory receptors. The functional impact of coreceptors on FA remains to be fully elucidated. Despite its importance, FA is infrequently assessed and incompletely understood. There is currently no consensus as to whether FA can be enhanced by optimized vaccine dose or boosting schedule. Recent findings suggest that FA is remarkably stable in vivo, possibly due to continued signaling modulation of critical receptors in the immune synapse. In this review, we provide an overview of the current knowledge and hypothesize that in vivo, codominant T cells constantly "equalize" their FA for similar function. We present a new model of constant FA regulation, and discuss practical implications for T-cell-based cancer immunotherapy