Regulation of T-Cell Chemotaxis by Programmed Death-Ligand 1 (PD-L1) in Dry Eye–Associated Corneal Inflammation

Purpose. Given that dry eye disease (DED) is associated with T cell–mediated inflammation of the ocular surface and that PD-L1 is an important negative or inhibitory regulator of immune responses constitutively expressed at high levels by corneal epithelial cells, the authors studied the expression and function of PD-L1 in DED. Methods. Dry eye was induced in untreated wild-type mice, PD-L1−/− mice, and wild-type mice treated with anti–PD-L1 antibody by exposing these mice to a desiccating environment in the controlled environment chamber modified with subcutaneous administration of scopolamine. Real-time PCR was used to quantify the expression of chemokine gene transcript levels of multiple CC and CXC chemokine ligands and receptors. Epifluorescence microscopy was used to evaluate corneal infiltration of CD3+ T cells after immunohistochemical staining. Results. The increased expression of specific chemokine ligands and receptors in PD-L1−/− corneas of normal mice is associated with significant increases in T-cell homing into these corneas. Similar, and more enhanced, increases in T-cell infiltration were observed in PD-L1−/− DED mice or DED mice treated with anti–PD-L1 antibody compared with controls. In addition, the authors found significantly decreased expression of PD-L1 by corneal epithelial cells in DED and significantly increased corneal fluorescein staining score with PD-L1 functional blockade using anti–PD-L1 antibody. Conclusions. Downregulation of corneal epithelial PD-L1 amplifies dry eye–associated corneal inflammation and epitheliopathy by increasing the expression of chemokine ligands and receptors that promote T-cell homing to the ocular surface

TIM-family Proteins Promote Infection of Multiple Enveloped Viruses through Virion-associated Phosphatidylserine

Human T-cell Immunoglobulin and Mucin-domain containing proteins (TIM1, 3, and 4) specifically bind phosphatidylserine (PS). TIM1 has been proposed to serve as a cellular receptor for hepatitis A virus and Ebola virus and as an entry factor for dengue virus. Here we show that TIM1 promotes infection of retroviruses and virus-like particles (VLPs) pseudotyped with a range of viral entry proteins, in particular those from the filovirus, flavivirus, New World arenavirus and alphavirus families. TIM1 also robustly enhanced the infection of replication-competent viruses from the same families, including dengue, Tacaribe, Sindbis and Ross River viruses. All interactions between TIM1 and pseudoviruses or VLPs were PS-mediated, as demonstrated with liposome blocking and TIM1 mutagenesis experiments. In addition, other PS-binding proteins, such as Axl and TIM4, promoted infection similarly to TIM1. Finally, the blocking of PS receptors on macrophages inhibited the entry of Ebola VLPs, suggesting that PS receptors can contribute to infection in physiologically relevant cells. Notably, infection mediated by the entry proteins of Lassa fever virus, influenza A virus and SARS coronavirus was largely unaffected by TIM1 expression. Taken together our data show that TIM1 and related PS-binding proteins promote infection of diverse families of enveloped viruses, and may therefore be useful targets for broad-spectrum antiviral therapies

Does wage rank affect employees' well-being?

How do workers make wage comparisons? Both an experimental study and an analysis of 16,000 British employees are reported. Satisfaction and well-being levels are shown to depend on more than simple relative pay. They depend upon the ordinal rank of an individual's wage within a comparison group. “Rank” itself thus seems to matter to human beings. Moreover, consistent with psychological theory, quits in a workplace are correlated with pay distribution skewness

CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells

CD40L has a well-established role in enhancing the immunostimulatory capacity of normal and malignant B cells, but a formulation suitable for clinical use has not been widely available. Like other TNF family members, in vivo and in vitro activity of CD40L requires a homotrimeric configuration, and growing evidence suggests that bioactivity depends on higher-order clustering of CD40. We generated a novel formulation of human recombinant CD40L (CD40L-Tri) in which the CD40L extracellular domain and a trimerization motif are connected by a long flexible peptide linker. We demonstrate that CD40L-Tri significantly expands normal CD19+ B cells by over 20- to 30-fold over 14 days and induces B cells to become highly immunostimulatory antigen-presenting cells (APCs). Consistent with these results, CD40L-Tri-activated B cells could effectively stimulate antigen-specific T responses (against the influenza M1 peptide) from normal volunteers. In addition, CD40L-Tri could induce malignant B cells to become effective APCs, such that tumor-directed immune responses could be probed. Together, our studies demonstrate the potent immune-stimulatory effects of CD40L-Tri on B cells that enable their expansion of antigen-specific human T cells. The potent bioactivity of CD40L-Tri is related to its ability to self-multimerize, which may be facilitated by its long peptide linker. Electronic supplementary material The online version of this article (doi:10.1007/s00262-012-1331-4) contains supplementary material, which is available to authorized users

New clues to the evolution of dwarf early-type galaxies

Surface photometry of 18 Virgo cluster dwarf elliptical (dE) and dwarf lenticular (dS0) galaxies, made by Gavazzi et al. (2001) in the H-band (1.65 micron) and in the B-band (0.44 micron), shows that the ratio of the effective radii of these stellar systems in the B- and H-band, r_{e B}/r_{e H}, ranges between 0.7 and 2.2. In particular, dwarf ellipticals and lenticulars with a red total color index B-H (i.e. with 3.2 < B-H < 4) have equal effective radii in these two pass-bands. By contrast, blue (i.e. with 2.5 < B-H < 3.1) dEs and dS0s have B-band effective radii about 50% longer than the H-band ones, on average. Consistently, strong negative gradients in B-H along the galactocentric radius are found to be associated with blue total colors. This trend is not found in a sample of 29 giant E and S0 galaxies of the Coma cluster with analogous data available in the literature. These early-type giants span a broad range in r_{e B}/r_{e H} (0.2--2.2), with a mean r_{e B}/r_{e H} of about 1.1, but a narrow range in (red) color (3.3 < B-H < 4.2). In these stellar systems, color gradients are usually interpreted as due either to age/metallicity gradients along the radial coordinate or to dust attenuation, whatever the total color of the system is. Assuming each of these three distinct interpretations of the origin of color gradients, we discuss the origin of the association of strong negative color gradients with blue colors found in the early-type dwarfs under study, in relation with current scenarios of formation and evolution of dE and dS0 galaxies.Comment: 12 pages, 8 Postscript figures, accepted to MNRA

Differentiated Regulation:the case of charities

The increasing number and influence of charities in the economy, evidence of mismanagement and the need for information for policymaking are all reasons for establishing charity regulators. Public interest and public choice theories explain charity regulation which aims to increase public trust and confidence in charities (and thus increase voluntarism and philanthropy) and to limit tax benefits to specific organisations and donors. Nevertheless, regulation is resource intensive, and growing pressure on government budgets requires efficiencies to be found. This study proposes regulation differentiated according to charities' main resource providers, to reduce costs and focus regulatory effort, and provides a feasible segmentation