Brief Definitive Report
Niche displacement of human leukemic stem cells uniquely allows their competitive replacement with healthy HSPCs
Spatial localization of primitive leukemic cells is restricted to niches shared with their normal counterparts, and their ability to retain occupancy of these niches is rivaled by normal HSPCs.
Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD
Ward et al. report retinal thinning in humans with progranulin mutations that precedes dementia onset, and an age-dependent retinal neurodegenerative phenotype in progranulin null mice. Nuclear depletion of TDP-43 precedes retinal neuronal loss and is accompanied by reduced GTPase Ran, with overexpression of Ran restoring nuclear TDP-43 and neuronal survival.
Naik et al. show that the deubiquitinating enzyme Usp9X is a regulator of T cell activation and its loss induces the development of a lupuslike autoimmune disease in mice.
Chemokine-coupled β2 integrin–induced macrophage Rac2–Myosin IIA interaction regulates VEGF-A mRNA stability and arteriogenesis
Monocytes are required for arteriogenesis after injury and one of their major roles is to produce VEGF; however, the mechanisms behind this have not been identified. Morrison et al. find a link between chemokine and integrin stimulation through Rac2 that involves myosin heavy chain to redistribute the RNA stabilizing protein HuR to augment VEGF expression.
Genetic impairment of plasmacytoid dendritic cells ameliorates autoantibody production and symptoms of SLE in mice.
Early, transient depletion of plasmacytoid dendritic cells ameliorates autoimmunity in a lupus model
Transient, genetic elimination of a specialized group of cells called plasmacytoid dendritic cells (pDCs) reverses many features of lupus in mice. Disease reduction was attributed in part to decreased expression of inflammatory molecules called interferons, which are produced primarily by pDCs.
The Src family kinases Hck, Fgr, and Lyn are critical for the generation of the in vivo inflammatory environment without a direct role in leukocyte recruitment
Kovács et al. examine the role of the Src family kinases Hck, Fgr, and Lyn in immune cell–mediated inflammation. Using arthritis and skin inflammation models, the authors show that mice lacking hematopoietic Hck, Fgr, and Lyn are protected from these inflammatory diseases, showing loss of myeloid cell recruitment and lack of inflammatory mediator production. Unexpectedly, the three kinases are dispensable for the intrinsic migratory ability of myeloid cells. These finding may have clinical implications in rheumatic and skin diseases.
Selective and strain-specific NFAT4 activation by the Toxoplasma gondii polymorphic dense granule protein GRA6
Ma et al. show that the Toxoplasma gondii polymorphic dense granule protein GRA6 triggers the activation of the host transcription factor NFAT4, thus affecting the host immune response and maximizing parasite virulence.
Exhaustion of bacteria-specific CD4 T cells and microbial translocation in common variable immunodeficiency disorders
Common variable immunodeficiency (CVID) is characterized by abnormally low levels of antibodies in the blood and dysfunctional immune cells called CD4+ T cells. Perreau et al. now show evidence that bacteria-fighting CD4+ T cells in these patients are in a state of exhaustion due to a constant leakage of normal gut bacteria into the bloodstream, possibly due to insufficient antibody levels.
Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction
In humans infected with hepatitis B or C, high expression of a protein called T-bet in virus-fighting immune cells is associated with spontaneous clearance of the virus. Absence of T-bet was more often seen in patients whose infections became chronic.
Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques
Five potent and broadly anti-HIV neutralizing monoclonal antibodies are able to block infection by two different SHIVs in monkeys. The authors show that antibodies targeting the outer glycan coat were the most effective and determined that titers of roughly 1:100 protected half the animals.
Conti et al. show that IL-17 is produced by tongue-resident populations of γδ T cells and nTh17 cells in response to oropharyngeal candidiasis in mice.
IKK-induced NF-κB1 p105 proteolysis is critical for B cell antibody responses to T cell–dependent antigen
Jacque et al. investigate the functions of NF-κB1 p105 and its associated NF-κB–binding partners in B cells, using a mutant mouse strain that carries a form of the NF-κB1 precursor that is resistant to IKK-induced proteolysis. They identify a critical B cell–intrinsic role for this IKK signaling pathway in the antigen-induced survival and differentiation of follicular mature B cells.
Germinal center B cell maintenance and differentiation are controlled by distinct NF-κB transcription factor subunits
Heise et al. find that the NF-κB subunits c-REL and RELA in B cells play distinct roles during the germinal center reaction. While RELA stimulates the emergence of plasma cells from the germinal center, c-REL supports maintenance of the reaction over time, possibly by inducing a metabolic gene program connected to cell proliferation.
WASH is required for the differentiation commitment of hematopoietic stem cells in a c-Myc–dependent manner
Xia et al. show that WASH deletion breaks the balance that controls self-renewal and differentiation of hematopoietic stem cells (HSCs). WASH assists the NURF complex to the promoter of c-Myc gene, and its loss perturbs LT-HSC differentiation by suppressing the transcriptional activation of c-Myc.