November 2014 | Volume 211, No. 12
Brief Definitive Reports
- Staphylococcus aureus infection induces protein A–mediated immune evasion in humans
Pauli et al. find that the active B cell response in patients infected with Staphylococcus aureus is predominately focused on a single antigen, SpA, which acts as a B cell superantigen. SpA-reactive antibodies dominate the response despite the presence of circulating B cells specific for other bacterial surface antigens.
- Sex steroid blockade enhances thymopoiesis by modulating Notch signaling
Velardi et al. show that sex steroids regulate thymopoiesis by directly modulating Notch signaling, and provide a novel clinical strategy to boost immune regeneration.
- GPR18 is required for a normal CD8αα intestinal intraepithelial lymphocyte compartment
G protein–coupled receptor 18 is required for accumulation of CD8α+ intraepithelial lymphocytes in the intestine.
- Enhanced HIV-1 immunotherapy by commonly arising antibodies that target virus escape variants
Klein et al. find that frequently arising antibodies that normally fail to control HIV-1 infection can synergize with passively transferred bNAbs to prevent the emergence of bNAb viral escape variants.
- Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice
William Murphy’s group at UC Davis previously found that systemic administration of stimulatory immunotherapy (IT) in aged mice resulted in the rapid induction of cytokine storm culminating in multi-organ pathology and rapid lethality. They now show that in addition to age, increased body fat is critical to this adverse reaction, as aged calorie-restricted mice demonstrate protection from IT-induced toxicity. In contrast, young obese mice succumb to cytokine storm, multi-organ pathology, and lethality after systemic IT administration.
- An inherited mutation in NLRC4 causes autoinflammation in human and mice
Kitamura et al. identify NLRC4 as causing familial cold autoinflammatory syndrome using whole exome sequencing on a family with multiple affected family members. They identify a mutation in the NOD domain and show that the mutant protein increases Nlrc4 oligomerization and is associated with increased IL-1β. Transgenic mice with the same NLRC4 mutation are shown to develop a similar FCAS-like syndrome.
- Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell–dependent inflammation
Wang et al. examine how influenza A virus causes GI symptoms. Intranasal infection in mice causes intestinal pathology via virally activated CD4 T cells in the lung up-regulating CCR9 and migrating to the intestine where they secrete IFN-γ that alters homeostasis of the microbiota. Subsequent induction of IL-15 aids differentiation into pathogenic Th17 cells in the gut.
- Identification of Cdca7 as a novel Notch transcriptional target involved in hematopoietic stem cell emergence
Guiu et al. use ChIP-on-chip analysis for the Notch partner RBPj, using embryonic tissue from the aorta-gonad-mesonephros region to identify potential novel Notch target genes involved in HSC emergence. They show that c-MYC–responsive gene Cdca7 is expressed in different HSC and progenitor subpopulations and that CDCA7 is important for maintaining the undifferentiated phenotype. Cdca7 acts downstream of Notch in HSCs in zebrafish, mouse, and human, indicating a highly conserved Notch/RBPj/Cdca7 axis in hematopoietic development.
- Limitation of immune tolerance–inducing thymic epithelial cell development by Spi-B–mediated negative feedback regulation
Akiyama et al. show that transcription factor Spi-B is up-regulated by RANKL to trigger mTEC differentiation. Osteoprotegerin is also induced by this signaling pathway and acts as a negative feedback loop to attenuate mTEC development and thymic T reg cells.
- Cytosolic carboxypeptidase CCP6 is required for megakaryopoiesis by modulating Mad2 polyglutamylation
Ye et al. identify cytosolic carboxypeptidase CCP6 as a protein required for the regulation of bone marrow megakaryopoiesis in mice. The authors find that Mad2 (a core component of spindle checkpoint in mitosis) is a substrate of CCP6 in megakaryocytes and is polyglutamylated by proteins TTLL6 and TTLL4, subsequently affecting the activity of Aurora B kinase. Mad2 is thus additionally implicated in megakaryopoiesis regulation.
- Antigen-specific expansion and differentiation of natural killer cells by alloantigen stimulation
Nabekura and Lanier provide evidence that alloantigen stimulation of mouse NK cells promotes the in vivo expansion and generation of memory-like NK cells. NK cells expressing the activating Ly49D receptor preferentially expand and differentiate when challenged with allogeneic cells in an inflammatory environment, but this can be suppressed if NK cells also express the inhibitory Ly49A receptor which recognizes the same ligand. Recall responses were driven by expression of activating Ly49 receptors and regulated by inhibitory MHC I receptors.
- Hrd1-mediated BLIMP-1 ubiquitination promotes dendritic cell MHCII expression for CD4 T cell priming during inflammation
Yang et al. demonstrate that Hrd1 plays an important role in DC induction of CD4 T cell immunity. The underlying mechanism involves the ability of Hrd1 to ubiquitinate and degrade BLIMP-1, thus releasing CIITA from transcriptional repression and promoting MHCII expression. As a consequence, Hrd1−/− DCs protect mice from MOG-induced experimental autoimmune encephalomyelitis.