T lymphocytes are an essential component of the immune response against HSV infection. We previously reported that T cells became functionally impaired or inactivated after contacting HSV-infected fibroblasts. In our current study, we investigate the mechanisms of inactivation. We report that HSV-infected fibroblasts or HSV alone can inactivate T cells by profoundly inhibiting TCR signal transduction. Inactivation requires HSV penetration into T cells but not de novo transcription or translation. In HSV-inactivated T cells stimulated through the TCR, phosphorylation of Zap70 occurs normally. However, TCR signaling is inhibited at linker for activation of T cells (LAT) and at steps distal to LAT in the TCR signal cascade including inhibition of calcium flux and inhibition of multiple MAPK. Inactivation of T cells by HSV leads to the reduced phosphorylation of LAT at tyrosine residues critical for TCR signal propagation. Treatment of T cells with tyrosine phosphatase inhibitors attenuates inactivation by HSV, and stimulus with a mitogen that bypasses LAT phosphorylation overcomes inactivation. Our findings elucidate a potentially novel method of viral immune evasion that could be exploited to better manage HSV infection, aid in vaccine design, or allow targeted manipulation of T cell function.

Elimination rate constants (k2), biological half-lives (t(1/2)), and the time required to reach 95% of steady-state (t95) are reported for 46 individual polycyclic aromatic hydrocarbons (PAHs) including both parent and alkyl homologues, for the freshwater unionid mussel, Elliptio complanata. Elimination rate constants generally follow first-order kinetics and range from 0.04/day (d) for perylene to 0.26/d for 2,6-dimethylnapthalene, half-lives range from 2.6 to 16.5 d, and t95 values range from 11.3 to 71.3 d. These values compare well with other k2, t(1/2), and t95 values reported in the literature for PAHs and other classes of hydrophobic organic contaminants. A linear regression of k2 versus log Kow demonstrates dependence of PAH elimination on hydrophobicity, as measured by an r2 value of 0.83, and produces the following regression equation: k2 = -0.06 (log Kow) + 0.44. This study provides evidence that mussels experiencing different forms of physiological stress (e.g., handling stress and fungal or bacterial growth) can exhibit large variation in toxicokinetic parameters. These results are particularly relevant to the extrapolation of laboratory results to field situations.

Background: The pleiotrophic cytokine interleukin (IL)-13 features prominently in allergic and inflammatory diseases. In allergic asthma, IL-13 is well established as an inducer of airway inflammation and tissue remodeling. We demonstrated previously that IL-13 induces release of transforming growth factor-α (TGFα) from human bronchial epithelial cells, with proliferation of these cells mediated by the autocrine/paracrine action of this growth factor. TGFα exists as an integral membrane protein and requires proteolytic processing to its mature form, with a disintegrin and metalloproteinase (ADAM)17 responsible for this processing in a variety of tissues.