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The transcription factor C/EBPα is required for granulopoiesis and frequently disrupted in human acute myeloid leukemia (AML). Here, we show disruption of C/EBPα blocks the transition from the common myeloid to the granulocyte/monocyte progenitor but is not required beyond this stage for terminal granulocyte maturation. C/EBPα-deficient hematopoietic stem cells (HSCs) have increased expression of...
GM-CSF promotes homeostasis of myeloid cells. We report that GM-CSF upregulates mRNA and protein production of the soluble form of membrane bound VEGF receptor-1 (sVEGFR-1) in human monocytes. This sVEGFR-1 was biologically active, as cell-free supernatants from GM-CSF-stimulated monocytes blocked detection of endogenously expressed VEGF and inhibited endothelial cell migration and tube formation,...
The role of the thymus in HIV infection has been a matter of considerable debate. A new study by in this issue of Immunity provides the mechanism for reduced thymic output in HIV infection while illuminating the impact of recent thymic emigrants on peripheral T cell homeostasis.
Escape from adaptive T cell immunity through transmutation of viral antigenic structure is a cardinal feature in the pathogenesis of SIV/HIV infection and a major obstacle to antiretroviral vaccine development. However, the molecular determinants of this phenomenon at the T cell receptor (TCR)-antigen interface are unknown. Here, we show that mutational escape is intimately linked to the structural...
CD11c hi dendritic cells (DC) play an essential role during the initiation of cell-mediated immunity. Recently, CD11c lo CD45RB hi DC with regulatory properties have been described. However, the origins of regulatory DC are poorly understood. Here, we show that spleen-derived stromal cells promote selective development of CD11c lo CD45RB + ...
TRAIL receptor (TRAIL-R) signaling has been implicated in inducing apoptosis in tumor cells, but little is understood about its physiological function. Here, we report the generation and characterization of TRAIL-R -/- mice, which develop normal lymphocyte populations but possess enhanced innate immune responses. TRAIL-R -/- mice exhibited increased clearance of...
The Polycomb group (PcG) gene Bmi-1 has recently been implicated in the maintenance of hematopoietic stem cells (HSC) from loss-of-function analysis. Here, we demonstrate that increased expression of Bmi-1 promotes HSC self-renewal. Forced expression of Bmi-1 enhanced symmetrical cell division of HSCs and mediated a higher probability of inheritance of stemness through cell division. Correspondingly,...
The supply of naive T cells by the thymus normally requires precursor T cell proliferation within the thymus and would be particularly important in the setting of HIV infection when both naive and memory T cells are progressively depleted. As a robust, quantitative index of intrathymic proliferation, the ratio of different T cell receptor excision circles (TRECs), molecular markers of distinct T cell...
Congenic strains of mice continue to reveal important insights into the immune system. , in this issue of Immunity, report on a genomic region that has a cluster of immune genes with different ancestral haplotypes influencing disease in a model of SLE.
Small RNAs of 21-23 nucleotides are powerful regulators of gene expression and play essential roles in biological processes that include development, maintenance of genome stability, and viral adaptive defense mechanisms. Such small RNAs are simple in design yet rich in biology and have captivated the attention of biologists in many fields. This review discusses the potential roles of small RNAs in...
The cause of common polygenic autoimmune diseases is not understood because of genetic and cellular complexity. Here, we pinpoint the action of a subset of autoimmune susceptibility loci in the NOD mouse strain linked to D1mit181, D2mit490, D7mit101, and D15mit229, which cause a generalized resistance to thymic deletion in vivo that applies equally to Aire-induced organ-specific gene products in the...
We recently identified a 3' region of the rad50 gene possessing strong enhancer activity as well as activity consistent with function as a locus control region (LCR) for the flanking Th2 cytokine genes. In this study, we identify several functional elements within this region by examining chromatin changes as well as activity in transgenic mice. We find within this region four DNase I hypersensitive...
DRAK2 is a member of the death-associated protein (DAP)-like family of serine/threonine kinases. Members of this family induce apoptosis in various cell types. DRAK2, in particular, is specifically expressed in T cells and B cells, and it is differentially regulated during T cell development. To determine whether DRAK2 regulates lymphocyte apoptosis, we produced Drak2 -/- mice. Contrary...
Susceptibility to autoimmunity in B6.Sle1b mice is associated with extensive polymorphisms between two divergent haplotypes of the SLAM/CD2 family of genes. The B6.Sle1b-derived SLAM/CD2 family haplotype is found in many other laboratory mouse strains but only causes autoimmunity in the context of the C57Bl/6 (B6) genome. Phenotypic analyses have revealed variations in the structure and expression...
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