Variants of the Bach2 gene are linked to vitiligo, celiac disease and type I diabetes, but the underlying immunological mechanisms are unknown. Here, we demonstrate that Bach2 plays crucial roles in maintaining T cell quiescence, and governing the differentiation, activation, and survival of foxp3+ Treg cells. Bach2-deficient T cells display spontaneous activation and produce elevated levels of TH1/TH2 type cytokines. Without Bach2, Treg cells exhibit diminished foxp3 expression, depleted numbers, hyper-activation, enhanced proliferation and profound loss of competitive fitness in vivo. Mechanistically, reduced survival of Bach2-deficient Treg cells was associated with reduced Bcl-2 and Mcl-1 levels and elevated Bim:Bcl-2 ratio. Additionally, Bach2 deficiency induced selective loss of Helios− foxp3+ Treg cells and a Treg cell transcriptome skewed towards the TH1/TH2 effector program at the expense of the Treg program. In vitro experiments confirmed that Bach2: (1) is indispensable for TCR/TGF-β-induced foxp3 expression and (2) mitigates aberrant differentiation of Treg cells by repression of the competing Gata3-driven TH2 effector program. Importantly, perturbations in the differentiation of induced Treg cells was linked to a fatal TH2 type chronic inflammatory lung disease in Bach2-deficient mice. Thus, Bach2 enforces T cell quiescence, promotes the development and survival of Treg lineage, restrains aberrant differentiation of Treg cells and protects against immune -mediated diseases.

Cells have a defense against latent human cytomegalovirus, but the viral UL138 protein inactivates it to allow lifelong persistence.

Cell proteins can restrict the replication of viruses. Here, we identify the cellular BclAF1 protein as a human cytomegalovirus restriction factor and describe two independent mechanisms the virus uses to decrease its steady-state levels. Immediately following infection, the viral pp71 and UL35 proteins, which are delivered to cells within virions, direct the proteasomal degradation of BclAF1. Although BclAF1 reaccumulates through the middle stages of infection, it is subsequently down-regulated at late times by miR-UL112-1, a virus-encoded microRNA. In the absence of BclAF1 neutralization, viral gene expression and replication are inhibited. These data identify two temporally and mechanistically distinct functions used by human cytomegalovirus to down-regulate a cellular antiviral protein.

Global cerebral ischemia (GCI) is one of the main causes of hippocampal neuronal death. Ischemic damage can be rescued by early blood reperfusion. However, under some circumstances reperfusion itself can trigger a cell death process that is initiated by the reintroduction of blood, followed by the production of superoxide, a blood–brain barrier (BBB) disruption and microglial activation. Protocatechuic acid (PCA) is a major metabolite of the antioxidant polyphenols, which have been discovered in green tea. PCA has been shown to have antioxidant effects on healthy cells and anti-proliferative effects on tumor cells. To test whether PCA can prevent ischemia-induced hippocampal neuronal death, rats were injected with PCA (30 mg/kg/day) per oral (p.o) for one week after global ischemia. To evaluate degenerating neurons, oxidative stress, microglial activation and BBB disruption, we performed Fluoro-Jade B (FJB), 4-hydroxynonenal (4HNE), CD11b, GFAP and IgG staining. In the present study, we found that PCA significantly decreased degenerating neuronal cell death, oxidative stress, microglial activation, astrocyte activation and BBB disruption compared with the vehicle-treated group after ischemia. In addition, an ischemia-induced reduction in glutathione (GSH) concentration in hippocampal neurons was recovered by PCA administration. Therefore, the administration of PCA may be further investigated as a promising tool for decreasing hippocampal neuronal death after global cerebral ischemia.

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