ON THE COVER
Using optic nerve injury as a neurodegeneration model, Norris et al. show that microglia are the key phagocytes that remove synaptic debris, and that this function of the microglia is mediated by the complement system and dependent on recognition of neurodegeneration. Image credit: iStock.com/eremin777. See page 1789.
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Regulating the regulator: Bhlhe40 directly keeps IL-10 in check
Huynh et al. and Yu et al. demonstrate that the transcription factor Bhlhe40 acts is a repressor of IL-10 production during infection with Mycobacterium tuberculosis or Toxoplasma gondii. Deletion of Bhlhe40 in both cases resulted in chronic infection and increased pathogen load as a consequence of increased IL-10 production.
A20 and ABIN-1 team up against intestinal epithelial cell death
A20 and its binding partner ABIN-1 are genetically linked to inflammatory diseases. In this issue of JEM, Kattah et al. demonstrate that simultaneous deletion in a mouse model leads to instantaneous cell death in the intestinal epithelium and mortality.
TRIMming TGF-β signals in Th17 cells
The precise downstream mediators of TGF-β signaling in Th17 and T reg cells remain unclear. In this issue of JEM, Tanaka et al. report that Trim33 transduces TGF-β signals in Th17 cells to generate an optimal proinflammatory cytokine profile.
Drawing on disorder: How viruses use histone mimicry to their advantage
Viruses mimic histone proteins to gain control over gene regulatory networks, maximize replication, and suppress host antiviral immunity.
Brief Definitive Report
Neuronal integrity and complement control synaptic material clearance by microglia after CNS injury
Norris et al. show that microglia are the key phagocytes in removal of synaptic debris in the dorsal lateral geniculate nucleus after optic nerve injury. This microglial function is dependent on recognition of neurodegeneration and is mediated by the complement system.
Effector CD4 T cells with progenitor potential mediate chronic intestinal inflammation
Effector CD4 T cells with progenitor properties are present during chronic intestinal inflammation, and these cells support the maintenance of disease. The expression of the glycosyltransferase ST6Gal-I by these cells promotes cell survival and TCF1 levels.
The transcription factor Bhlhe40 is a switch of inflammatory versus antiinflammatory Th1 cell fate determination
The balance between inflammatory IFN-γ and antiinflammatory IL-10 plays a critical role in modulating type 1 immune responses. Yu et al. show that the transcription factor Bhlhe40 serves as a molecular switch between inflammatory and antiinflammatory Th1 cells.
Bhlhe40 is an essential repressor of IL-10 during Mycobacterium tuberculosis infection
This study demonstrates that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is essential during Mycobacterium tuberculosis infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection.
A20 and ABIN-1 synergistically preserve intestinal epithelial cell survival
A20 (TNFAIP3) and ABIN-1 (TNIP1), two candidate inflammatory bowel disease (IBD) susceptibility genes, preserve intestinal homeostasis by cooperatively restricting intestinal epithelial cell death. A20 and ABIN-1 synergistically restrict both TNF-dependent and TNF-independent cell death.
Trim33 mediates the proinflammatory function of Th17 cells
Trim33, a modulator of TGF-β signaling, mediates the proinflammatory function of Th17 cells by the promotion of IL-17 and repression of IL-10 production. These cytokine expressions are regulated through an epigenetic mechanism in cooperation with Smad2 and ROR-γ.
The Rho regulator Myosin IXb enables nonlymphoid tissue seeding of protective CD8+ T cells
Moalli et al. combine in vitro CD8+ T cell motility analysis with intravital imaging of mouse tissues to identify the actomyosin regulator Myo9b as a central player for nonlymphoid tissue infiltration during adaptive immune responses by facilitating crossing of tissue barriers.
Itraconazole targets cell cycle heterogeneity in colorectal cancer
Chemotherapy-resistant dormant colorectal cancer cells are a differentiated cell that can de-differentiate and proliferate, accounting for tumor recurrence. Itraconazole induces all tumor cells, including those dormant, to proliferate then enter senescence and is effective in multiple preclinical assays.
Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies
Adaptive responses have been demonstrated to limit activity to targeted therapies. Saei et al. show that loss of USP28/FBW7-mediated BRAF degradation is observed in a proportion of melanoma patients and can be responsible for resistance through upregulation of MAPK signaling pathway.
JDP2: An oncogenic bZIP transcription factor in T cell acute lymphoblastic leukemia
Mansour et al. demonstrate that JDP2, a bZIP transcription factor, is overexpressed in patients with high-risk T cell acute lymphoblastic leukemia (T-ALL). JDP2 initiates T-ALL in a zebrafish model and leads to steroid resistance in vivo through direct regulation of MCL1.
Dissection of progenitor compartments resolves developmental trajectories in B-lymphopoiesis
Jensen et al. report the identification and characterization of novel lymphoid progenitor populations in the mouse bone marrow. The work resolves the complexity of the BLP/pre-pro–B/Fraction A compartments and provides a developmental trajectory for early B cell development.