Impaired immunity is a fundamental obstacle to successful allogeneic hematopoietic cell transplantation. Mature graft T cells are thought to provide protection from infections early after transplantation, but can cause life-threatening graft-vs.-host disease. Human CMV is a major pathogen after transplantation. We studied reactivity against the mouse homologue, murine CMV (MCMV), in lethally irradiated mice given allogeneic purified hematopoietic stem cells (HSCs) or HSCs supplemented with T cells or T-cell subsets. Unexpectedly, recipients of purified HSCs mounted superior antiviral responses compared with recipients of HSC plus unselected bulk T cells. Furthermore, supplementation of purified HSC grafts with CD8 + memory or MCMV-specific T cells resulted in enhanced antiviral reactivity. Posttransplantation lymphopenia promoted massive expansion of MCMV-specific T cells when no competing donor T cells were present. In recipients of pure HSCs, naive and memory T cells and innate lymphoid cell populations developed. In contrast, the lymphoid pool in recipients of bulk T cells was dominated by effector memory cells. These studies show that pure HSC transplantations allow superior protective immunity against a viral pathogen compared with unselected mature T cells. This reductionist transplant model reveals the impact of graft composition on regeneration of host, newly generated, and mature transferred T cells, and underscores the deleterious effects of bulk donor T cells. Our findings lead us to conclude that grafts composed of purified HSCs provide an optimal platform for in vivo expansion of selected antigen-specific cells while allowing the reconstitution of a naive T-cell pool.graft-vs.-host reactions | hematopoietic stem cell transplantation | immune reconstitution | lymphopenia induced proliferation | M45-tetramer
SUMMARY Cytoplasmic dynein is responsible for many aspects of cellular and subcellular movement. LIS1, NudE, and NudEL are dynein interactors initially implicated in brain developmental disease, but now known to be required in cell migration, nuclear, centrosomal, and microtubule transport, mitosis, and growth cone motility. Identification of a specific role for these proteins in cytoplasmic dynein motor regulation has remained elusive. We find that NudE stably recruits LIS1 to the dynein holoenzyme molecule, where LIS1 interacts with the motor domain during the prepowerstroke state of the dynein crossbridge cycle. NudE abrogates dynein force production, whereas LIS1 alone or with NudE induces a persistent-force dynein state that improves ensemble function of multiple dyneins for transport under high-load conditions. These results likely explain the requirement for LIS1 and NudE in transport of nuclei, centrosomes, chromosomes, the microtubule cytoskeleton, and the particular sensitivity of migrating neurons to reduced LIS1 expression.
Summary The microtubule motor Kinesin-1 plays central roles in intracellular transport. It has been widely assumed that many cellular cargos are moved by multiple Kinesins and that cargos with more motors move faster and for longer distances; concrete evidence, however, is sparse. Here we rigorously test these notions using lipid droplets in Drosophila embryos: We first employ antibody inhibition, genetics, biochemistry, and particle tracking to demonstrate that Kinesin-1 mediates plus-end droplet motion. We then measure how variation in Kinesin-1 expression affects the forces driving individual droplets and estimate the number of Kinesins actively engaged per droplet. Unlike in vitro, increased motor number results neither in longer travel distances nor higher velocities. Our data suggest that cargos in vivo can simultaneously engage multiple Kinesins and that transport properties are largely unaffected by variation in motor number. Apparently, higher-order regulatory mechanisms rather than motor number per se dominate cargo transport in vivo.
We report atomic-scale characterization of the pseudogap state in a high-Tc superconductor, Bi2Sr2CaCu2O(8+delta). The electronic states at low energies within the pseudogap exhibit spatial modulations having an energy-independent incommensurate periodicity. These patterns, which are oriented along the copper-oxygen bond directions, appear to be a consequence of an electronic ordering phenomenon, the observation of which correlates with the pseudogap in the density of electronic states. Our results provide a stringent test for various ordering scenarios in the cuprates, which have been central in the debate on the nature of the pseudogap and the complex electronic phase diagram of these compounds.
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