Ion release is an important environmental behavior of silver nanoparticles (AgNPs), and characterization of Ag(+) release is critical for understanding the environmental fate, transport, and biological impacts of AgNPs. The ion release kinetics of AgNPs with three primary diameters (20, 40, and 80 nm) were studied by dispersing them in quarter-strength Hoagland medium at two initial concentrations (300 and 600 μg/L). Ag(+) release rates were found to depend on primary particle size and concentration, when other environmental factors (e.g., dissolved oxygen and protons) were kept constant. A kinetic model was developed to describe the Ag(+) release based on the hard sphere theory using the Arrhenius equation. The model fitted the experimental data well with correlation coefficients of 0.97-0.99, and the model usefully interpreted the dependence of ion release kinetics on the primary particle size and concentration. Moreover, the effects of environmental factors (e.g., dissolved oxygen, pH, temperature, and salinity) potentially can be interpreted as well. This model provides fundamental insight into the ion release kinetics of AgNPs in aqueous environments, allowing us to better understand and predict the nanotoxicity of AgNPs.

SUMMARY Herpes Zoster (shingles) causes significant morbidity in immune compromised hosts and older adults. While a vaccine is available for prevention of shingles, its efficacy declines with age. To help to understand the mechanisms driving vaccinal responses, we constructed a multiscale, multifactorial response network (MMRN) of immunity in healthy young and older adults immunized with the live attenuated shingles vaccine Zostavax®. Vaccination induces robust antigen-specific antibody, plasmablasts and CD4+ T cells, yet limited CD8+ T cell and antiviral responses. The MMRN reveals striking associations between orthogonal datasets such as transcriptomic and metabolomics signatures, cell populations and cytokine levels, and identifies immune and metabolic correlates of vaccine immunity. Networks associated with inositol phosphate, glycerophospholipids and sterol metabolism are tightly coupled with immunity. Critically, the sterol regulatory binding protein 1 and its targets are key integrators of antibody and T follicular cell responses. Our approach is broadly applicable to study human immunity, and can help to identify predictors of efficacy as well as mechanisms controlling immunity to vaccination.

Human herpesviruses are important causes of potentially severe chronic infections for which T cells are believed to be necessary for control. In order to examine the role of virus-specific CD8 T cells against Varicella Zoster Virus (VZV), we generated a comprehensive panel of potential epitopes predicted in silico and screened for T cell responses in healthy VZV seropositive donors. We identified a dominant HLA-A*0201-restricted epitope in the VZV ribonucleotide reductase subunit 2 and used a tetramer to analyze the phenotype and function of epitope-specific CD8 T cells. Interestingly, CD8 T cells responding to this VZV epitope also recognized homologous epitopes, not only in the other α-herpesviruses, HSV-1 and HSV-2, but also the γ-herpesvirus, EBV. Responses against these epitopes did not depend on previous infection with the originating virus, thus indicating the cross-reactive nature of this T cell population. Between individuals, the cells demonstrated marked phenotypic heterogeneity. This was associated with differences in functional capacity related to increased inhibitory receptor expression (including PD-1) along with decreased expression of co-stimulatory molecules that potentially reflected their stimulation history. Vaccination with the live attenuated Zostavax vaccine did not efficiently stimulate a proliferative response in this epitope-specific population. Thus, we identified a human CD8 T cell epitope that is conserved in four clinically important herpesviruses but that was poorly boosted by the current adult VZV vaccine. We discuss the concept of a “pan-herpesvirus” vaccine that this discovery raises and the hurdles that may need to be overcome in order to achieve this.

Vaccines against mucosally invasive, intracellular pathogens must induce a myriad of immune responses in order to provide optimal mucosal and systemic protection, including CD4+ T cells, CD8+ T cells and antibody-producing B cells. In general, CD4+ T cells are known to provide important helper functions for both CD8+ T cell and B cell responses. However, the relative importance of CD4+ T cells, CD8+ T cells and B cells for mucosal protection is less clearly defined. We have studied these questions in detail using the murine model of Trypanosoma cruzi infection. Despite our initial hypothesis that mucosal antibodies would be important, we show that B cells are critical for systemic, but not mucosal, T. cruzi protective immunity. B cell deficient mice developed normal levels of CD8+ effector T cell responses early after mucosal T. cruzi infection and T. cruzi trans-sialidase vaccination. However, after highly virulent systemic challenge, T. cruzi immune mice lacking T. cruzi-specific B cells failed to control parasitemia or prevent death. Mechanistically, T. cruzi-specific CD8+ T cells generated in the absence of B cells expressed increased PD-1 and Lag-3 and became functionally exhausted after high-level T. cruzi systemic challenge. T. cruzi immune serum prevented CD8+ T cell functional exhaustion and reduced mortality in mice lacking B cells. Overall, these results demonstrate that T. cruzi-specific B cells are necessary during systemic, but not mucosal, parasite challenge.