Formidable Defenses In Utero.

A developing human embryo encounters a multitude of threatening scenarios in the womb. How does the fetus defend itself throughout gestation? A new study by McGovern et al. provides remarkable insight into maternal-fetal immunotolerance.

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality.

Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1-/- donors. PD-L1-deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1-/- donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell-mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD.

Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells.

Human respiratory syncytial virus (hRSV) is the leading cause of bronchiolitis and pneumonia in young children worldwide. The recurrent hRSV outbreaks and reinfections are the cause of a significant public health burden and associate with an inefficient antiviral immunity, even after disease resolution. Although several mouse- and human cell-based studies have shown that hRSV infection prevents naïve T-cell activation by antigen-presenting cells, the mechanism underlying such inhibition remains unknown. Here, we show that the hRSV nucleoprotein (N) could be at least partially responsible for inhibiting T-cell activation during infection by this virus. Early after infection, the N protein was expressed on the surface of epithelial and dendritic cells, after interacting with trans-Golgi and lysosomal compartments. Further, experiments on supported lipid bilayers loaded with peptide-MHC (pMHC) complexes showed that surface-anchored N protein prevented immunological synapse assembly by naive CD4(+) T cells and, to a lesser extent, by antigen-experienced T-cell blasts. Synapse assembly inhibition was in part due to reduced T-cell receptor (TCR) signaling and pMHC clustering at the T-cell-bilayer interface, suggesting that N protein interferes with pMHC-TCR interactions. Moreover, N protein colocalized with the TCR independently of pMHC, consistent with a possible interaction with TCR complex components. Based on these data, we conclude that hRSV N protein expression at the surface of infected cells inhibits T-cell activation. Our study defines this protein as a major virulence factor that contributes to impairing acquired immunity and enhances susceptibility to reinfection by hRSV.

Immunology on chip: promises and opportunities.

Microfluidics has facilitated immunological studies by enhancing speed, efficiency and sensitivity of current analysis methods. It offers miniaturization of current laboratory equipment, and enables analysis of clinical samples without the need for sophisticated infrastructure. More importantly, microfluidics offers unique capabilities; including conducting multiple serial or parallel tasks as well as providing complex and precisely controlled environmental conditions that are not achievable using conventional laboratory equipment. Microfluidics is a promising technology for fundamental and applied immunological studies, allowing generation of high throughput, robust and portable platforms, opening a new area of automation in immunology.

PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis.

Immune responses to persistent viral infections and cancer often fail because of intense regulation of antigen-specific T cells-a process referred to as immune exhaustion. The mechanisms that underlie the induction of exhaustion are not completely understood. To gain novel insights into this process, we simultaneously examined the dynamics of virus-specific CD8(+) and CD4(+) T cells in the living spleen by two-photon microscopy (TPM) during the establishment of an acute or persistent viral infection. We demonstrate that immune exhaustion during viral persistence maps anatomically to the splenic marginal zone/red pulp and is defined by prolonged motility paralysis of virus-specific CD8(+) and CD4(+) T cells. Unexpectedly, therapeutic blockade of PD-1-PD-L1 restored CD8(+) T cell motility within 30 min, despite the presence of high viral loads. This result was supported by planar bilayer data showing that PD-L1 localizes to the central supramolecular activation cluster, decreases antiviral CD8(+) T cell motility, and promotes stable immunological synapse formation. Restoration of T cell motility in vivo was followed by recovery of cell signaling and effector functions, which gave rise to a fatal disease mediated by IFN-γ. We conclude that motility paralysis is a manifestation of immune exhaustion induced by PD-1 that prevents antiviral CD8(+) T cells from performing their effector functions and subjects them to prolonged states of negative immune regulation.

In vivo assessment of hemocompatibility of a ventricular assist device in healthy swine.

OBJECTIVE: To assess the hemocompatible performance of a novel implantable pneumatic ventricular assist device (VAD, Innovamédica, México) in healthy swine. The aim of this pilot study was first, to determine if short-term VAD implantation elicited remarkable inflammatory response above that expected from surgical trauma; and second, to assess if heparinized or passivated VAD coatings, in combination with systemic anticoagulant or antiaggregant therapies, modified the VAD's hemocompatible performance. METHODS: Hemodynamic, physicologic, inflammatory and histological parameters were measured in 27 pigs receiving VAD support for six hours, testing combinations of heparinized or passivated VAD coatings and systemic anticoagulant/ antiaggregant therapies. Mean concentrations of interleukin -1 B (IL-1B), interleukin -6 (IL-6), C-reactive protein (CRP), or thrombin-antithrombin III (TAT) complexes (coagulation indicator) were measured from blood. ANOVA statistics were employed. RESULTS: No substantial increases in mean IL -1B, IL-6, CRP, or TAT were obtained during VAD support. Hemodynamic ans physiologic parameters were normal. We found no evidence of thromboembolisms or micro-infarctions in heart and lung samples. No major coaguli/deposits were found in VAD compartments. Overall, no remarkable differences in measurements were found using heparinized, passivated, or uncoated VAD, or with systemic anticoagulation, antiaggregant therapy, or no treatment. CONCLUSIONS: Our findings demonstrate, firstly, that during the time-period tested, the VAD elicited negligible inflammation above the effects of surgical trauma; and secondly, that little coagulation was observed upon VAD support in any of the cases tested. Contemplating further validation studies, our data indicate that the Innovamédica VAD is a highly hemocompatible system.

In vivo assessment of hemocompatibility of a ventricular assist device in healthy swine / Evaluación de la hemocompatibilidad in vivo (cerdos sanos) de un dispositivo de asistencia ventricular

Objective: To assess the hemocompatible performance of a novel implantable pneumatic ventricular assist device (VAD, Innovamédica, México) in healthy swine. The aim of this pilot study was first, to determine if short-term VAD implantation elicited a remarkable inflammatory response above that expected from surgical trauma; and second, to assess if heparinized or passivated VAD coatings, in combination with systemic anticoagulant or antiaggregant therapies, modified the VAD's hemocompatible performance. Methods: Hemodynamic, physiologic, inflammatory and histological parameters were measured in 27 pigs receiving VAD support for six hours, testing combinations of heparinized or passivated VAD coatings and systemic anticoagulant/ antiaggregant therapies. Mean concentrations of interleukin-1 β (IL-16), interleukin-6 (IL-6), C-reactive protein (CRP), or thrombin-antithrombin III (TAT) complexes (coagulation indicator) were measured from blood. ANOVA statistics were employed. Results: No substantial increases in mean IL-1β, IL-6, CRP, or TAT were obtained during VAD support. Hemodynamic and physiologic parameters were normal. We found no evidence of thromboembolisms or micro-infarctions in heart and lung samples. No major coaguli/deposits were found in VAD compartments. Overall, no remarkable differences in measurements were found using heparinized, passivated, or uncoated VAD, or with systemic anticoagulation, antiaggregant therapy, or no treatment. Conclusions: Our findings demonstrate, firstly, that during the time-period tested, the VAD elicited negligible inflammation above the effects of surgical trauma; and secondly, that little coagulation was observed upon VAD support in any of the cases tested. Contemplating further validation studies, our data indicate that the Innovamédica VAD is a highly hemocompatible system.

Objetivo: Evaluar la hemocompatibilidad de un nuevo dispositivo de asistencia ventricular (DAV, Innovamédica, México) neumático e implantable, en cerdos sanos. En este estudio piloto se propuso determinar primero, si la implantación a corto plazo del DAV suscitaría una respuesta inflamatoria por encima de aquella esperada tras trauma quirúrgico; segundo, evaluar si recubrimientos heparinizados o pasivos del DAV, en combinación con tratamientos sistémicos anticoagulantes o antiplaquetarios, modificarían la hemocompatibilidad del DAV. Métodos: Se midieron parámetros hemodinámicos, fisiológicos, inflamatorios e histológicos en 27 cerdos recibiendo soporte del DAV durante seis horas, evaluando combinaciones de recubrimientos heparinizados y pasivos del DAV, y terapias sistémicas anticoagulantes / antiplaquetarias. Se obtuvieron, a partir de sangre, las concentraciones promedio de interleucina-1 (IL-1β), interleucina-6 (IL-6), proteína C reactiva (PCR) y los complejos trombina-antitrombina III (TAT) (índice de coagulación). Se emplearon análisis estadísticos ANOVA. Resultados: No se observaron incrementos importantes en los niveles promedio de IL-1β, IL-6, PCR, o TAT durante soporte del DAV. Los parámetros hemodinámicos y fisiológicos fueron normales. No existió evidencia alguna de trom-boembolias o micro-infartos en muestras de miocardio y pulmón. No se encontraron coágulos o depósitos mayores en compartimentos del DAV. En general, no se apreciaron diferencias notables de mediciones utilizando dispositivos con recubrimiento heparinizado, pasivo o sin recubrimiento, en conjunto con terapia sistémica anticoagulante, antiplaquetaria o sin ella. Conclusiones: Nuestros hallazgos demuestran, primero, que durante el periodo de medición experimental, el DAV suscitó una respuesta inflamatoria mínima por encima de los efectos de trauma quirúrgico, y; segundo, en todos los casos evaluados, se observaron escasos o inexistentes efectos de coagulación durante soporte ventricular. Contemplando estudios adicionales de validación, nuestros datos indican que el DAV Innovamédica es un sistema altamente hemocompatible.