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The functional activity of integrins is dynamically regulated by T cell receptor stimulation and by protein kinase C (PKC). We report a novel function for the PKC effector protein kinase D1 (PKD1) in integrin activation. Constitutively active and kinase-inactive PKD1 mutants lacking the PKD1 pleckstrin homology (PH) domain block phorbol ester- and TCR-mediated activation and clustering of β1 integrins...
The mechanisms that mediate the recruitment of Th1 and Th2 lymphocytes in vivo are poorly understood. We demonstrate that the mechanisms by which exogenously produced CD4 + Th1 and Th2 cells roll and adhere in Con A-inflamed liver microcirculation differ dramatically: Th1 cells use α 4 β 1 -integrin and Th2 cells use the vascular adhesion protein (VAP)-1. P-selectin plays no...
Aire promotes the tolerization of thymocytes by inducing the expression of a battery of peripheral-tissue antigens in thymic medullary epithelial cells. We demonstrate that the cellular mechanism by which Aire exerts its tolerance-promoting function is not primarily positive selection of regulatory T cells, but rather negative selection of T effector cells. Surprisingly, supplementing its influence...
DNA and RNA stimulate the mammalian innate immune system through activation of Toll-like receptors (TLRs). DNA containing methylated CpG motifs, however, is not stimulatory. Selected nucleosides in naturally occurring RNA are also methylated or otherwise modified, but the immunomodulatory effects of these alterations remain untested. We show that RNA signals through human TLR3, TLR7, and TLR8, but...
The contribution of a self-antigen to marginal-zone B lymphocytes is described in this issue (Wen et al., 2005). Other interpretations of these important findings are considered here.
Understanding the regulation of immune responses is central for control of autoimmune and infectious disease. In murine models of autoimmunity and chronic inflammatory disease, potent regulatory T lymphocytes have recently been characterized. Despite an explosion of interest in these cells, their relevance to human disease has been uncertain. In a longitudinal study of malaria sporozoite infection...
Vav1 is a guanine nucleotide exchange factor (GEF) for Rho-family GTPases, which is activated by tyrosine phosphorylation following TCR stimulation. Vav1-deficient mice have defects in positive and negative selection of thymocytes as well as TCR-induced proliferation in mature T cells, demonstrating a critical role for Vav1 in transducing TCR signals. Binding of phospholipids to the PH domain of Vav1...
In many host-parasite systems, regulatory T cells (CD4 + , CD25 + , FOXP3 + ) have been shown to modulate cellular immunity and pathology. In this issue of Immunity, Walther et al. have now shown that following experimental malaria infection of human volunteers, enhanced TGF-β and T reg responses are associated with a faster parasite growth rate. The study demonstrates that...
Certain microbes evade host innate immunity by killing activated macrophages with the help of virulence factors that target prosurvival pathways. For instance, infection of macrophages with the TLR4-activating bacterium Bacillus anthracis triggers an apoptotic response due to inhibition of p38 MAP kinase activation by the bacterial-produced lethal toxin. Other pathogens induce macrophage apoptosis...
Questions regarding T cell development have recently received much attention, but the earliest intrathymic differentiation steps in adult mice have remained controversial. Three new papers together show that for at least some thymus-settling precursors, the loss of B lineage potential occurs in the thymus, and Notch acts on multipotent progenitors early after thymic entry.
The c-Myb transcription factor is crucial during definitive hematopoiesis. However, the embryonic lethality of Myb traditional null mutations has precluded analysis of c-Myb function in lymphocytes. Using tissue-specific inactivation at the Myb locus, we demonstrate that loss of Myb causes a partial block during B cell development at the pro-B to pre-B cell transition, resulting in greatly decreased...
Intercellular signals can be transmitted through neuronal synapses or through gap junctions, with the latter mediating transmission of calcium fluxes and small molecules between cells. We show here that a third form of communication between cells can be mediated by tunneling nanotubules (TNT). When myeloid-lineage dendritic cells and monocytes are triggered to flux calcium by chemical or mechanical...
Antigen receptor-mediated signaling is critical for the development and survival of B cells. However, it has not been established whether B cell development requires a signal from self-ligand engagement at the immature stage, a process known as “positive selection.” Here, using a monoclonal B cell receptor (BCR) mouse line, specific for the self-Thy-1/CD90 glycoprotein, we demonstrate that BCR crosslinking...
Dendritic cells (DCs) are major constituents of peripheral tissues, where they control immunity to foreign and self-antigens. The process of continuous DC renewal under homeostatic conditions is largely undefined. Here, we demonstrate that CD14 + DC precursors, either derived from CD34 + hematopoietic progenitor cells or isolated from blood, were attracted by the chemokine CXCL14,...
Perforin delivers granzymes to induce target-cell apoptosis. At high concentrations, perforin multimerizes in the plasma membrane to form pores. However, whether granzymes enter target cells via membrane pores is uncertain. Here we find that perforin at physiologically relevant concentrations and during cell-mediated lysis creates pores in the target-cell membrane, transiently allowing Ca 2+ ...
Toll-like receptors (TLRs) trigger inflammatory signaling in macrophages and enrich on phagosomes, suggesting that TLRs may directly influence phagosome formation and maturation. However, in this issue of Immunity, Yates and Russell use carefully defined particles and quantitative methodology to measure phagosome maturation and find no effect of TLR signaling on the process.
Mature recirculating B cells are generally assumed to exist in follicular niches in secondary lymphoid organs, and these cells mediate T-dependent humoral immune responses. We show here that a large proportion of mature B lymphocytes occupy an anatomically and functionally distinct perisinusoidal niche in the bone marrow. Perisinusoidal B cells circulate freely, as revealed by parabiosis studies....
Conventional understanding of CD4 T cell development is that the MHC class II molecules on cortical thymic epithelial cell are necessary for positive selection, as demonstrated in mouse models. Clinical data, however, show that hematopoietic stem cells reconstitute CD4 T cells in patients devoid of MHC class II. Additionally, CD4 T cells generated from human stem cells in immunocompromised mice were...
Despite numerous reports on MHC class II expression by T cells from a wide spectrum of mammalian species including humans, the biological relevance of this phenomenon has never been tested with appropriately designed animal models. To address this issue, we developed mouse models in which immature thymocytes are the only positively selecting antigen-presenting cells in the thymus. In these mice, CD4...
The intrinsic refractoriness of naive T cells for cytokine production is counteracted by cells of the innate immune system. Upon sensing danger via Toll-like receptors, these cells upregulate T cell costimulatory molecules and secrete cytokines that enhance T cell activation. We show that cytokine-mediated priming of naive T cells requires the NF-κB family member c-Rel. In resting naive cells c-Rel...
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