Altered Homeostasis of CD4+ Memory T Cells in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Chronic Graft-versus-Host Disease Enhances T Cell Differentiation and Exhausts Central Memory T Cell Pool

AbstractAn increased risk of late infection is a serious complication after allogeneic hematopoietic stem cell transplantation (AHSCT), especially for recipients with defective CD4+ T cell recovery. Although chronic graft-versus-host disease (cGVHD) negatively influences CD4+ T cell reconstitution, the mechanisms leading to this defect are not well understood. We found that the proportion of CD27− CD4+ T cells was remarkably increased in ASHCT recipients with cGVHD or with repetitive infectious episodes. Isolated CD27− CD4+ T cells from ASHCT recipients had significantly shortened telomere length, displayed enhanced vulnerability to activation-induced cell death, and showed extremely reduced clonal diversity, when compared with CD27− CD4+ T cells from healthy donors. Also, CD27+ CD4+ T cells from AHSCT recipients easily lost their expression of CD27 in response to antigen stimulation regardless of cGVHD status. Taken together, these data indicate that homeostasis of memory CD4+ T cells from AHSCT recipients is altered, and that they easily transit into CD27− effector memory T cells. Increased in vivo T cell stimulation observed in recipients with cGVHD further promotes the transition to effector memory cells, a change that decreases the central memory CD4+ T cell pool and consequently weakens the recipient’s defense against persistently infecting pathogens

The CD70-CD27 interaction during the stimulation with dendritic cells promotes naive CD4+ T cells to develop into T cells producing a broad array of immunostimulatory cytokines in humans

CD70 expressed on dendritic cells (DCs) has been shown to play a critical role in inducing effective CD8+ T cell responses and a Th1 response in mice. However, it has not been extensively examined whether human primary DCs express CD70 and whether the CD70–CD27 interaction promotes naive CD4+ T cells to acquire the ability to produce effector cytokines during the DC–T cell interaction in humans. Here, we show that human myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells stimulated with CD40 ligand together with pro-inflammatory cytokines or Toll-like receptor ligands express CD70. Thymic stromal lymphopoietin plus prostaglandin E2 also induced CD70 on mDCs. Naive CD4+ T cells stimulated with DCs but not with anti-CD3/CD28 microbeads expressed CD70. Stimulation with CD70 together with anti-CD3/CD28 microbeads imparted the ability to produce Th1 (IFN-), Th2 (IL-4, IL-5, IL-13) cytokines, IL-2 and tumor necrosis factor- to naive CD4+ T cells. The production of IFN- was associated with the induction of T-bet. Naive CD4+ T cells stimulated with mDCs acquired an enhanced ability to produce a broad array of immunostimulatory cytokines in a CD70-dependent manner. These data suggest that human CD70 expressed on mDCs and activated T cells transmits a ‘basal level’ signal, rather than a ‘polarizing’ signal, to naive CD4+ T cells, in that CD70 promotes the development of CD4+ T cells that produce a variety of effector cytokines including both Th1 and Th2 types, thus contributing to the enhancement of a broad spectrum of immune responses

Cor Triatriatum in the Adult with Aortic Stenosis and Mitral Stenosis

Background：Cor triatriatum is a rare congenital cardiac anomaly, in which the left atrium or right atrium is separated by an abnormal fibromuscular membrane with one or more restrictive orifices. This condition typically presents in infancy or early childhood and can be associated with other cardiac anomalies.Case presentation：A 75-year-old woman was admitted for exertional dyspnea with moderate aortic and mitral stenosis. As cor triatriatum was revealed by a computed tomography and echocardiography, she was referred to our department for surgery. Aortic valve replacement, mitral valve replacement and excision of the membranous septum in the left atrium was performed. This report presents an incidental findings of cor triatriatum with aortic stenosis, moderate mitral stenosis in septuagenarian.Conclusion：We encountered a rare case of cor triatriatum with aortic stenosis and mitral stenosis in septuagenarian. She was incidentally diagnosed by rheumatic aortic and mitral stenosis which had advanced to moderate level

Gene expression in a canine basilar artery vasospasm model: a genome-wide network-based analysis

To investigate the changes of gene expression on the cerebral vasospasm after subarachnoid hemorrhage, we used genome-wide microarray for a canine double-hemorrhage model and analyzed the data by using a network-based analysis. Six dogs were assigned to two groups of three animals: control and hemorrhage. The effects were assessed by the changes in gene expressions in the artery 7 days after the first blood injection. Among 23,914 genes, 447 and 66 genes were up-regulated more than two- and fivefold, respectively, and 332 and 25 genes were down-regulated more than two- and fivefold, respectively. According to gene ontology, genes related to cell communication (P = 5.28E-10), host–pathogen interaction (7.65E-8), and defense–immunity protein activity (0.000183) were significantly overrepresented. The top high-level function for the merged network derived from the network-based analysis was cell signaling, revealing that the subgroup that regulates the quantity of Ca2+ to have the strongest association significance (P = 4.75E-16). Canine microarray analysis followed by gene ontology profiling and connectivity analysis identified several functional groups and individual genes responding to cerebral vasospasm. Ca2+ regulation may play a key role in these gene expression changes and may be involved in the pathogenesis of cerebral vasospasm

Chemogenetic sensory fMRI reveals behaviorally relevant bidirectional changes in primate somatosensory network

手と足の感覚は、実は脳の中でつながっていた --脳障害による活動変化の広がりを見ることで常識を覆す発見、脳機能・疾患機序の理解へ前進--. 京都大学プレスリリース. 2021-10-21.Concurrent genetic neuromodulation and functional magnetic resonance imaging (fMRI) in primates has provided a valuable opportunity to assess the modified brain-wide operation in the resting state. However, its application to link the network operation with behavior still remains challenging. Here, we combined chemogenetic silencing of the primary somatosensory cortex (SI) with tactile fMRI and related behaviors in macaques. Focal chemogenetic silencing of functionally identified SI hand region impaired grasping behavior. The same silencing also attenuated hand stimulation-evoked fMRI signal at both the local silencing site and the anatomically and/or functionally connected downstream grasping network, suggesting altered network operation underlying the induced behavioral impairment. Furthermore, the hand region silencing unexpectedly disinhibited foot representation with accompanying behavioral hypersensitization. These results demonstrate that focal chemogenetic silencing with sensory fMRI in macaques unveils bidirectional network changes to generate multifaceted behavioral impairments, thereby opening a pivotal window toward elucidating the causal network operation underpinning higher brain functions in primates

On-Orbit Demonstration of Innovative Multifunctional Membrane Structure for Ultra-Lightweight Solar Arrays and Array Antennas by 3U CubeSat OrigamiSat-1

The 3U CubeSat OrigamiSat-1’s deployable membrane structure is 1m-by-1m in size after deployment and is stowed in less than 1U CubeSat (10cm-by-10cm-by-8cm), including a hold-and-release mechanism. The major significance of the structural concept is that it allows the attachment of thin-film devices, such as thin-film solar cells or flexible substrates for antennas throughout the membrane. This was achieved by two features: (i) use of textile and (ii) invention of hybrid boom made of tubular carbon composite and metal convex tape. In addition, a visual membrane measurement system consisting of stereo cameras was developed. This paper describes the new technologies developed for this CubeSat

Chemogenetic dissection of the primate prefronto-subcortical pathways for working memory and decision-making

「何を買うんだっけ」と「どれにしよう」を処理する2つの脳回路を明らかに --霊長類の生体脳で神経経路を可視化・操作する技術で解明、高次脳機能の理解へ大きく前進--. 京都大学プレスリリース. 2021-06-24.The primate prefrontal cortex (PFC) is situated at the core of higher brain functions via neural circuits such as those linking the caudate nucleus and mediodorsal thalamus. However, the distinctive roles of these prefronto-subcortical pathways remain elusive. Combining in vivo neuronal projection mapping with chemogenetic synaptic silencing, we reversibly dissected key pathways from dorsolateral part of the PFC (dlPFC) to the dorsal caudate (dCD) and lateral mediodorsal thalamus (MDl) individually in single monkeys. We found that silencing the bilateral dlPFC-MDl projections, but not the dlPFC-dCD projections, impaired performance in a spatial working memory task. Conversely, silencing the unilateral dlPFC-dCD projection, but not the unilateral dlPFC-MDl projection, altered preference in a decision-making task. These results revealed dissociable roles of the prefronto-subcortical pathways in working memory and decision-making, representing the technical advantage of imaging-guided pathway-selective chemogenetic manipulation for dissecting neural circuits underlying cognitive functions in primates