CD39 Expression Identifies Terminally Exhausted CD8+ T Cells.

Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion.

Autophagy flux inhibition, G2/M cell cycle arrest and apoptosis induction by ubenimex in glioma cell lines.

This study aimed to investigate whether ubenimex could work as an anti-tumor drug alone in glioma cells and figure out the underlying potential mechanisms. Ubenimex is widely used as an adjunct therapy in multiple solid cancers. However, it is rarely used to treat glioblastoma. The function of ubenimex in enhancing JQ1 treatment sensitivity of glioma cells by blocking autophagic degradation of HEXIM1 was previously studied. However, the detailed mechanism of autophagy regulation by ubenimex remains unclear. The U87 and U251 cell lines were treated with different doses of ubenimex. Cell viability was measured by using the WST-8 assay. Cell death was assessed using trypan blue staining and flow cytometry. The migration and invasive ability of glioma cells were examined by transwell migration/invasion assay. LC3-GFP-RFP was used to measure autophagic flux. Protein expression was assessed by Western blot analysis. Autophagosomes were evaluated using the transmission electron microscopy. Moreover, cell cycle arrest (PI Staining) was measured by flow cytometry. Results revealed that ubenimex inhibited cell proliferation as well as migration/invasion in glioma cells. Besides, ubenimex increased glioma cell death via autophagic flux inhibition. Meanwhile, ubenimex induced G2/M phase arrest and apoptosis, and this effect was accompanied by the decreased levels of p-Akt, indicating the role of ubenimex in the regulation of glioma cell proliferation and metastasis. To sum up, this study concluded that ubenimex could work as an anti-tumor drug alone in the glioma cells via inhibiting autophagic flux and inducing G2/M arrest as well as apoptosis.

Protective effect of resveratrol against pressure overload-induced heart failure.

Transverse aortic constriction (TAC)-induced pressure overload (PO) causes adverse cardiac remodeling and dysfunction that progresses to heart failure (HF). The purpose of this study was to determine whether the potent antioxidant, resveratrol, significantly attenuates PO-induced HF in wild-type mice. Male C57BL6 mice were subjected to either sham or TAC surgery. One group of TAC mice was given daily resveratrol treatment. Echocardiographic, biometric, and immunohistological analyses were performed on the three groups of mice. All echocardiographic parameters demonstrated significantly greater adverse cardiac remodeling and dysfunction in the TAC compared to the sham mice. Increases in the ratios of heart weight (HW)/body weight (BW) and lung weight (LW)/BW and a sharp decline in the percentage of ejection fraction and fractional shortening were found in TAC relative to sham mice. Likewise, the TAC protocol increased markers of oxidative stress, cardiac hypertrophy, inflammation, fibrosis, hypoxia, and apoptosis. These pathological changes were significantly attenuated by resveratrol treatment. Resveratrol treatment significantly attenuates the adverse cardiac remodeling and dysfunction produced by the TAC protocol in C57/BL6 mice and this activity is mediated, at least in part, by the inhibition of oxidative stress and inflammation indicating a therapeutic potential of resveratrol in HF.