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B cells are activated in vivo after the B cell receptors (BCRs) bind to antigens captured on the surfaces of antigen-presenting cells. Antigen binding results in BCR microclustering and signaling; however, the molecular nature of the signaling-active BCR clusters is not well understood. Using single-molecule imaging techniques, we provide evidence that within microclusters, the binding of monovalent...
Development of T helper (Th) 17 cells requires transforming growth factor (TGF)-β and interleukin (IL)-6 and is independent of the Th1 pathway. Although T cells that produce interferon (IFN)-γ are a recognized feature of Th17 cell responses, mice deficient for STAT4 and T-bet—two prototypical Th1 transcription factors—are protected from autoimmunity associated with Th17 pathogenesis. To examine the...
In this issue of Immunity, Lee et al. (2009) and Wei et al. (2009) each investigate the stability of T helper cell lineages and find that commitment to these fates is more plastic than previously appreciated.
Tapasin is a glycoprotein critical for loading major histocompatibility complex (MHC) class I molecules with high-affinity peptides. It functions within the multimeric peptide-loading complex (PLC) as a disulfide-linked, stable heterodimer with the thiol oxidoreductase ERp57, and this covalent interaction is required to support optimal PLC activity. Here, we present the 2.6 Å resolution structure...
Interleukin-17A (IL-17A) is a cytokine produced by T helper 17 (Th17) cells and plays important roles in the development of inflammatory diseases. Although IL-17F is highly homologous to IL-17A and binds the same receptor, the functional roles of this molecule remain largely unknown. Here, we demonstrated with Il17a −/− , Il17f −/− , and Il17a −/− Il17f −/− mice that...
Follicular dendritic cells (FDCs) are important for the induction of protective T cell-dependent humoral responses, but their contribution to autoimmunity remains elusive. Here, gene-targeted interruption of FDC development was combined with the K/BxN mouse model of arthritis. We found that FDCs were essential for autoantibody production through two distinct but cooperative functions. In a T cell-independent...
The ability of macrophages to clear pathogens and elicit a sustained immune response is regulated by various cytokines, including interferon-γ (IFN-γ). To investigate the molecular mechanisms by which IFN-γ modulates phagosome functions, we profiled the changes in composition, abundance, and phosphorylation of phagosome proteins in resting and activated macrophages by using quantitative proteomics...
The role of basophils, the rarest of blood granulocytes, in host immunity has been a mystery. Long considered the poor relative of mast cells, basophils have received much recent attention because of the availability of new reagents and models that reveal unique properties of these cells. Basophils are known to have distinct roles in allergic hypersensitivity reactions and in the immune response to...
Apoptotic death of hepatocytes, a contributor to many chronic and acute liver diseases, can be a consequence of overactivation of the immune system and is often mediated by TNFα. Injection with lipopolysaccharide (LPS) plus the transcriptional inhibitor D(+)-galactosamine (GalN) or mitogenic T cell activation causes fatal hepatocyte apoptosis in mice, which is mediated by TNFα, but the effector mechanisms...
Notch1 signaling is required for T cell development and has been implicated in fate decisions in the thymus. We showed that Notch1 deletion in progenitor T cells (pro-T cells) revealed their latent developmental potential toward becoming conventional and plasmacytoid dendritic cells. In addition, Notch1 deletion in pro-T cells resulted in large numbers of thymic B cells, previously explained by T-to-B...
In this issue of Immunity, Ishigame et al. (2009) show that interleukin-17A (IL-17A) mediates autoimmunity whereas both IL-17A and IL-17F are required for mucosal immunity. IL-17A may be more pathologic by inducing proinflammatory cytokines.
Mucosal immunoglobulin A (IgA) secreted by local plasma cells (PCs) is a critical component of mucosal immunity. Although IgA class switching can occur at mucosal sites, high-affinity PCs are optimally generated in germinal centers (GCs) in a T cell-dependent fashion. However, how CD4 + helper T cells induce mucosal-homing IgA-PCs remains unclear. Here, we show that transforming growth factor...
In this issue of Immunity, Feyerabend et al. (2009) report that Delta-like 4, acting on Notch 1, prevents pro-T cells from differentiating into dendritic cells and B cells. In addition, in the absence of Notch 1, B cells in the thymus arose from a cell-extrinsic pathway.
Multipotential naive CD4 + T cells differentiate into distinct lineages including T helper 1 (Th1), Th2, Th17, and inducible T regulatory (iTreg) cells. The remarkable diversity of CD4 + T cells begs the question whether the observed changes reflect terminal differentiation with heritable epigenetic modifications or plasticity in T cell responses. We generated genome-wide histone H3...
It is well established that sustained increases in cyclic AMP (cAMP) such as those triggered by forskolin inhibit T cell activation. We describe here an unexpected phenomenon: in T cells, a transient cAMP increase triggered by the interaction with a dendritic cell strongly potentiates T cell receptor (TCR) signaling. We discovered this effect by examining the molecular basis of the adhesion-dependent...
In this issue of Immunity, Dong et al. (2009) describe the protein crystal structure heterodimer of tapasin and ERp57, which helps visualize the function of these proteins in loading of peptide antigens onto MHC class I molecules as part of the peptide loading complex within the endoplasmic reticulum.
In this issue of Immunity, Conche et al. (2009) define an antigen-independent signaling pathway that is dependent on cyclic adenosine monophosphate and extracellular signal-regulated kinase and T cells for subsequent T cell antigen receptor signaling.
Foxp3 + regulatory T (Treg) cells limit pathogenic immune responses to self-antigens and foreign antigens. An essential role for microRNA (miRNA) in the maintenance and function of Treg cells, revealed by the Treg cell-specific Dicer ablation, raised a question as to a specific miRNA contribution. We found that Foxp3 controlled the elevated miR155 expression required for maintaining Treg cell...
FAS belongs to the subgroup of the tumor necrosis factor receptor (TNF-R) family that contains an intracellular “death domain” and triggers apoptosis. Its physiological ligand FASL is a member of the TNF cytokine family. Studies with mutant mice and cells from human patients have shown that FAS plays critical roles in the immune system, including the killing of pathogen-infected cells and the death...
Effector (Teff) and regulatory (Treg) T cells produce cytokines that balance immunity and immunopathology at sites of infection. It is not known how this balance is achieved. Here, we show that Treg and Teff cells specific for the same foreign peptide:major histocompatibility complex II (pMHCII) ligand accumulated preferentially in a subcutaneous site injected with the relevant antigen plus an adjuvant...
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