Single crystal elasticity of majoritic garnets: Stagnant slabs and thermal anomalies at the base of the transition zone

The elastic properties of two single crystals of majoritic garnet (Mg3.24Al1.53Si3.23O12 and Mg3.01Fe0.17Al1.68Si3.15O12), have been measured using simultaneously single-crystal X-ray diffraction and Brillouin spectroscopy in an externally heated diamond anvil cell with Ne as pressure transmitting medium at conditions up to ∼30 GPa and ∼600 K. This combination of techniques makes it possible to use the bulk modulus and unit-cell volume at each condition to calculate the absolute pressure, independently of secondary pressure calibrants. Substitution of the majorite component into pyrope garnet lowers both the bulk (Ks) and shear modulus (G). The substitution of Fe was found to cause a small but resolvable increase in Ks that was accompanied by a decrease in ∂Ks/∂P, the first pressure derivative of the bulk modulus. Fe substitution had no influence on either the shear modulus or its pressure derivative. The obtained elasticity data were used to derive a thermo-elastic model to describe Vs and Vp of complex garnet solid solutions. Using further elasticity data from the literature and thermodynamic models for mantle phase relations, velocities for mafic, harzburgitic and lherzolitic bulk compositions at the base of Earth's transition zone were calculated. The results show that Vs predicted by seismic reference models are faster than those calculated for all three types of lithologies along a typical mantle adiabat within the bottom 150 km of the transition zone. The anomalously fast seismic shear velocities might be explained if laterally extensive sections of subducted harzburgite-rich slabs pile up at the base of the transition zone and lower average mantle temperatures within this depth range

Single-crystal elasticity of majoritic garnets: stagnant slabs and thermal anomalies at the base of the transition zone

The elastic properties of two single crystals of majoritic garnet (Mg3.24Al1.53Si3.23O12 and Mg3.01Fe0.17Al1.68Si3.15O12), have been measured using simultaneously single-crystal X-ray diffraction and Brillouin spectroscopy in an externally heated diamond anvil cell with Ne as pressure transmitting medium at conditions up to 3c30 GPa and 3c600 K. This combination of techniques makes it possible to use the bulk modulus and unit-cell volume at each condition to calculate the absolute pressure, independently of secondary pressure calibrants. Substitution of the majorite component into pyrope garnet lowers both the bulk (Ks) and shear modulus (G). The substitution of Fe was found to cause a small but resolvable increase in Ks that was accompanied by a decrease in 02Ks/ 02P, the first pressure derivative of the bulk modulus. Fe substitution had no influence on either the shear modulus or its pressure derivative. The obtained elasticity data were used to derive a thermo-elastic model to describe Vs and Vp of complex garnet solid solutions. Using further elasticity data from the literature and thermodynamic models for mantle phase relations, velocities for mafic, harzburgitic and lherzolitic bulk compositions at the base of Earth's transition zone were calculated. The results show that Vs predicted by seismic reference models are faster than those calculated for all three types of lithologies along a typical mantle adiabat within the bottom 150 km of the transition zone. The anomalously fast seismic shear velocities might be explained if laterally extensive sections of subducted harzburgite-rich slabs pile up at the base of the transition zone and lower average mantle temperatures within this depth range

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

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

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