Notch signaling during human T cell development

Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our current understanding of how Notch signaling is activated and used during human T cell development. First, we set the stage by describing the developmental steps that make up human T cell development before describing the expression profiles of Notch receptors, ligands, and target genes during this process. To delineate stage-specific roles for Notch signaling during human T cell development, we subsequently try to interpret the functional Notch studies that have been performed in light of these expression profiles and compare this to its suggested role in the mouse

Inhibitor of DNA Binding 3 Limits Development of Murine Slam-Associated Adaptor Protein-Dependent “Innate” γδ T cells

Id3 is a dominant antagonist of E protein transcription factor activity that is induced by signals emanating from the alphabeta and gammadelta T cell receptor (TCR). Mice lacking Id3 were previously shown to have subtle defects in positive and negative selection of TCRalphabeta+ T lymphocytes. More recently, Id3(-/-) mice on a C57BL/6 background were shown to have a dramatic expansion of gammadelta T cells.Here we report that mice lacking Id3 have reduced thymocyte numbers but increased production of gammadelta T cells that express a Vgamma1.1+Vdelta6.3+ receptor with restricted junctional diversity. These Vgamma1.1+Vdelta6.3+ T cells have multiple characteristics associated with "innate" lymphocytes such as natural killer T (NKT) cells including an activated phenotype, expression of the transcription factor PLZF, and rapid production of IFNg and interleukin-4. Moreover, like other "innate" lymphocyte populations, development of Id3(-/-) Vgamma1.1+Vdelta6.3+ T cells requires the signaling adapter protein SAP.Our data provide novel insight into the requirements for development of Vgamma1.1+Vdelta6.3+ T cells and indicate a role for Id3 in repressing the response of "innate" gammadelta T cells to SAP-mediated expansion or survival

Immune Response to Mycobacterium tuberculosis Infection in the Parietal Pleura of Patients with Tuberculous Pleurisy

The T lymphocyte-mediated immune response to Mycobacterium tuberculosis infection in the parietal pleura of patients with tuberculous pleurisy is unknown. The aim of this study was to investigate the immune response in the parietal pleura of tuberculous pleurisy compared with nonspecific pleuritis. We have measured the numbers of inflammatory cells particularly T-cell subsets (Th1/Th2/Th17/Treg cells) in biopsies of parietal pleura obtained from 14 subjects with proven tuberculous pleurisy compared with a control group of 12 subjects with nonspecific pleuritis. The number of CD3+, CD4+ and CCR4+ cells and the expression of RORC2 mRNA were significantly increased in the tuberculous pleurisy patients compared with the nonspecific pleuritis subjects. The number of toluidine blue+ cells, tryptase+ cells and GATA-3+ cells was significantly decreased in the parietal pleura of patients with tuberculous pleurisy compared with the control group of nonspecific pleuritis subjects. Logistic regression with receiver operator characteristic (ROC) analysis for the three single markers was performed and showed a better performance for GATA-3 with a sensitivity of 75%, a specificity of 100% and an AUC of 0.88. There was no significant difference between the two groups of subjects in the number of CD8, CD68, neutrophil elastase, interferon (IFN)-γ, STAT4, T-bet, CCR5, CXCR3, CRTH2, STAT6 and FOXP3 positive cells. Elevated CD3, CD4, CCR4 and Th17 cells and decreased mast cells and GATA-3+ cells in the parietal pleura distinguish patients with untreated tuberculous pleurisy from those with nonspecific pleuritis

Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment

During T cell development, multipotent progenitors relinquish competence for other fates and commit to the T cell lineage by turning on Bcl11b, which encodes a transcription factor. To clarify lineage commitment mechanisms, we followed developing T cells at the single-cell level using Bcl11b knock-in fluorescent reporter mice. Notch signaling and Notch-activated transcription factors collaborate to activate Bcl11b expression irrespectively of Notch-dependent proliferation. These inputs work via three distinct, asynchronous mechanisms: an early locus 'poising' function dependent on TCF-1 and GATA-3, a stochastic-permissivity function dependent on Notch signaling, and a separate amplitude-control function dependent on Runx1, a factor already present in multipotent progenitors. Despite their necessity for Bcl11b expression, these inputs act in a stage-specific manner, providing a multitiered mechanism for developmental gene regulation

The European Hematology Association Roadmap for European Hematology Research: a consensus document

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients

The European Hematology Association Roadmap for European Hematology Research. A Consensus Document

Abstract The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at Euro 23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine sections in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients. Received December 15, 2015. Accepted January 27, 2016. Copyright © 2016, Ferrata Storti Foundatio

T-cell identity and epigenetic memory

T-cell development endows cells with a flexible range of effector differentiation options, superimposed on a stable core of lineage-specific gene expression that is maintained while access to alternative hematopoietic lineages is permanently renounced. This combination of features could be explained by environmentally responsive transcription factor mobilization overlaying an epigenetically stabilized base gene expression state. For example, "poising" of promoters could offer preferential access to T-cell genes, while repressive histone modifications and DNA methylation of non-T regulatory genes could be responsible for keeping non-T developmental options closed. Here, we critically review the evidence for the actual deployment of epigenetic marking to support the stable aspects of T-cell identity. Much of epigenetic marking is dynamically maintained or subject to rapid modification by local action of transcription factors. Repressive histone marks are used in gene-specific ways that do not fit a simple, developmental lineage-exclusion hierarchy. We argue that epigenetic analysis may achieve its greatest impact for illuminating regulatory biology when it is used to locate cis-regulatory elements by catching them in the act of mediating regulatory change