Heart-specific CD4
+
T cells have been implicated in development and progression of myocarditis in mice and in humans. Here, using mouse models of experimental autoimmune myocarditis (EAM) we ...investigated the role of heart non-specific CD4
+
T cells in the progression of the disease. Heart non-specific CD4
+
T cells were obtained from DO11.10 mice expressing transgenic T cell receptor recognizing chicken ovalbumin. We found that heart infiltrating CD4
+
T cells expressed exclusively effector (
T
eff
) phenotype in the EAM model and in hearts of patients with lymphocytic myocarditis. Adoptive transfer experiments showed that while heart-specific
T
eff
infiltrated the heart shortly after injection, heart non-specific
T
eff
effectively accumulated during myocarditis and became the major heart-infiltrating CD4
+
T cell subset at later stage. Restimulation of co-cultured heart-specific and heart non-specific CD4
+
T cells with alpha-myosin heavy chain antigen showed mainly Th1/Th17 response for heart-specific
T
eff
and up-regulation of a distinct set of extracellular signalling molecules in heart non-specific
T
eff
. Adoptive transfer of heart non-specific
T
eff
in mice with myocarditis did not affect inflammation severity at the peak of disease, but protected the heart from adverse post-inflammatory fibrotic remodelling and cardiac dysfunction at later stages of disease. Furthermore, mouse and human
T
eff
stimulated in vitro with common gamma cytokines suppressed expression of profibrotic genes, reduced amount of α-smooth muscle actin filaments and decreased contraction of cardiac fibroblasts. In this study, we provided a proof-of-concept that heart non-specific
T
eff
cells could effectively contribute to myocarditis and protect the heart from the dilated cardiomyopathy outcome.
Alterations in Ca2+ homeostasis have been reported in several in vitro and in vivo studies using mice expressing the Alzheimer's disease–associated transgenes, presenilin and the amyloid precursor ...protein (APP). While intense research focused on amyloid-β–mediated functions on neuronal Ca2+ handling, the physiological role of APP and its close homolog APLP2 is still not fully clarified. We now elucidate a mechanism to show how APP and its homolog APLP2 control neuronal Ca2+ handling and identify especially the ectodomain APPsα as an essential regulator of Ca2+ homeostasis. Importantly, we demonstrate that the loss of APP and APLP2, but not APLP2 alone, impairs Ca2+ handling, the refill of the endoplasmic reticulum Ca2+ stores, and synaptic plasticity due to altered function and expression of the SERCA-ATPase and expression of store-operated Ca2+ channel–associated proteins Stim1 and Stim2. Long-term AAV-mediated expression of APPsα, but not acute application of the recombinant protein, restored physiological Ca2+ homeostasis and synaptic plasticity in APP/APLP2 cDKO cultures. Overall, our analysis reveals an essential role of the APP family and especially of the ectodomain APPsα in Ca2+ homeostasis, thereby highlighting its therapeutic potential.
The cytokine interleukin (IL)-7 exerts essential roles in lymph node (LN) organogenesis and lymphocyte development and homeostasis. Recent studies have identified lymphatic endothelial cells (LECs) ...as a major source of IL-7 in LNs. Here, we report that LECs not only produce IL-7, but also express the IL-7 receptor chains IL-7Rα and CD132. Stimulation with recombinant IL-7 enhanced LEC in vitro activity and induced lymphangiogenesis in the cornea of wild-type (WT) mice. Whereas in IL-7Rα−/− mice, dermal lymphatic vessels (LVs) were abnormally organized and lymphatic drainage was compromised, transgenic overexpression of IL-7 in mice resulted in an expanded dermal LV network with increased drainage function. Moreover, systemic treatment with recombinant IL-7 enhanced lymphatic drainage in the skin of WT mice and of mice devoid of lymphocytes. Experiments in IL-7Rα−/− bone marrow chimeras demonstrated that the drainage-enhancing activity of IL-7 was exclusively dependent on IL-7Rα expression in stromal but not in hematopoietic cells. Finally, near-infrared in vivo imaging performed in IL-7Rα−/− mice revealed that the pumping activity of collecting vessels was normal but fluid uptake into lymphatic capillaries was defective. Overall, our data point toward an unexpected new role for IL-7 as a potential autocrine mediator of lymphatic drainage.
•Afferent lymphatic vessels express interleukin-7.•Interleukin-7 supports lymphatic drainage.
More than 500 million people worldwide are persistently infected with hepatitis B virus or hepatitis C virus. Although both viruses are poorly cytopathic, persistence of either virus carries a risk ...of chronic liver inflammation, potentially resulting in liver steatosis, liver cirrhosis, end-stage liver failure or hepatocellular carcinoma. Virus-specific T cells are a major determinant of the outcome of hepatitis, as they contribute to the early control of chronic hepatitis viruses, but they also mediate immunopathology during persistent virus infection. We have analyzed the role of platelet-derived vasoactive serotonin during virus-induced CD8+ T cell-dependent immunopathological hepatitis in mice infected with the noncytopathic lymphocytic choriomeningitis virus. After virus infection, platelets were recruited to the liver, and their activation correlated with severely reduced sinusoidal microcirculation, delayed virus elimination and increased immunopathological liver cell damage. Lack of platelet-derived serotonin in serotonin-deficient mice normalized hepatic microcirculatory dysfunction, accelerated virus clearance in the liver and reduced CD8+ T cell-dependent liver cell damage. In keeping with these observations, serotonin treatment of infected mice delayed entry of activated CD8+ T cells into the liver, delayed virus control and aggravated immunopathological hepatitis. Thus, vasoactive serotonin supports virus persistence in the liver and aggravates virus-induced immunopathology.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The spatiotemporal regulation of immune responses in the lymph node (LN) depends on its sophisticated tissue architecture, consisting of several subcompartments supported by distinct fibroblastic ...stromal cells (FSCs). However, the intricate details of stromal structures and associated FSC subsets are not fully understood. Using several gene reporter mice, we sought to discover unrecognized stromal structures and FSCs in the LN. The four previously identified FSC subsets in the cortex are clearly distinguished by the expression pattern of reporters including PDGFRβ, CCL21-ser, and CXCL12. Herein, we identified a unique FSC subset expressing both CCL21-ser and CXCL12 in the deep cortex periphery (DCP) that is characterized by preferential B cell localization. This subset was clearly different from CXCL12
LepR
FSCs in the medullary cord, which harbors plasma cells. B cell localization in the DCP was controlled chiefly by CCL21-ser and, to a lesser extent, CXCL12. Moreover, the optimal development of the DCP as well as medulla requires B cells. Together, our findings suggest the presence of a unique microenvironment in the cortex-medulla boundary and offer an advanced view of the multi-layered stromal framework constructed by distinct FSC subsets in the LN.
The extremely slow compaction dynamics of wet granular assemblies is studied experimentally. The cohesion, due to capillary bridges between neighboring grains, is tuned using different liquids having ...specific surface tension values. The compaction dynamics of a cohesive packing obeys an inverse logarithmic law, like most dry random packings. However, the characteristic relaxation time τ grows strongly with cohesion. A model, based on free volume kinetic equations and the presence of a capillary energy barrier, is able to reproduce quantitatively the experimental curves.
This paper is an original exploration of the wide structural, compositional and formal similarities between Friedrich Dürrenmatt's successful play The Visit (1956) and the post-western film Bad Day ...at Black Rock (1955). Locating both works within the context of their recent history (World War II) and their own time (1950s), this comparative analysis argues that their particular deconstructions and revisions of the ›national myths‹ of their countries of origin reveal the paradigm of collective guilt as a fundamental commonality of the pair.
Auxin-mediated activation of secondary growth and subsequent KNOX/BEL expression coincide with active storage metabolism in xylem parenchyma cells of the cassava tuberous root.
Abstract
Cassava ...storage roots are among the most important root crops worldwide, and represent one of the most consumed staple foods in sub-Saharan Africa. The vegetatively propagated tropical shrub can form many starchy tuberous roots from its stem. These storage roots are formed through the activation of secondary root growth processes. However, the underlying genetic regulation of storage root development is largely unknown. Here we report distinct structural and transcriptional changes occurring during the early phases of storage root development. A pronounced increase in auxin-related transcripts and the transcriptional activation of secondary growth factors, as well as a decrease in gibberellin-related transcripts were observed during the early stages of secondary root growth. This was accompanied by increased cell wall biosynthesis, most notably increased during the initial xylem expansion within the root vasculature. Starch storage metabolism was activated only after the formation of the vascular cambium. The formation of non-lignified xylem parenchyma cells and the activation of starch storage metabolism coincided with increased expression of the KNOX/BEL genes KNAT1, PENNYWISE, and POUND-FOOLISH, indicating their importance for proper xylem parenchyma function.
Floodplain forests have become rare in Europe due to anthropogenic changes. A critical aspect of their restoration is reintroducing flooding via dike relocation, as implemented at the Elbe River near ...Lenzen/Germany. How forest development is influenced by dike relocation is still unclear and difficult to predict. Inside the dike relocation area at the Elbe River, most trees were planted. Due to high tree mortality, we asked if the relative elevation of the planted trees and thus the number of flooding days inside the relocation area was comparable to the prevailing flooding regime in the surrounding active floodplain. Therefore, the positions of Ulmus laevis, Quercus robur, and Crataegus monogyna individuals were recorded using a DGPS and merged with a digital terrain model. Subsequently, relative elevations and numbers of flooding days per year and growing season (averages for 2011–2017) were calculated. The most flooding tolerant species, U. laevis, occurred at the lowest sites and tolerated the highest number of flooding days, followed by Q. robur, and finally by the least flooding tolerant species C. monogyna. All three species occurred at lower sites inside the dike relocation area and were exposed to longer flooding durations compared to sites outside the area. This was due to the complex morphology of this area and its special flooding and flow dynamics, which differed from the conditions in the surrounding active floodplain. Although the mean flooding duration was within the growth range of hardwood floodplain forests (Ficario‐Ulmetum), most individuals may not have established at the planted sites under natural conditions. Therefore, we recommend not relying only on plantings but also allowing natural succession. Then, species that can cope with the hydrological site characteristics may also establish in the long term.
Abstract
Fibroblastic reticular cells (FRCs) determine the organization of lymphoid organs and control immune cell interactions. While the cellular and molecular mechanisms underlying of FRC ...differentiation in lymph nodes and the splenic white pulp have been elaborated to some extent, in Peyer’s patches (PPs) they remain elusive. Using a combination of single-cell transcriptomics and cell fate-mapping in advanced mouse models, we found that PP formation in the mouse embryo is initiated by an expansion of perivascular FRC precursors, followed by FRC differentiation from subepithelial progenitors. Single-cell transcriptomics and cell fate-mapping confirmed the convergence of perivascular and subepithelial FRC lineages. Furthermore, lineage-specific loss and gain-of-function approaches revealed that the two FRC lineages synergistically direct PP organization, maintain intestinal microbiome homeostasis and control anti-coronavirus immune responses in the gut. Collectively, this study reveals a distinct mosaic patterning program that generates key stromal cell infrastructures for the control of intestinal immunity.
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