Highlights d Lipophilic statins and lipophilic bisphosphonates are potent vaccine adjuvants d Modulation of post-translational protein prenylation confers adjuvanticity d Decreased protein prenylation augments antigen preservation and presentation d Statin-or bisphosphonate-mediated vaccination synergizes with anti-PD1 against cancer

Graphical Abstract Highlights d The crystal structure of HMBPP-bound intracellular BTN3A1 was determined at 1.97 Å d HMBPP forms hydrogen bonds with H 351 for efficient Vg9Vd2 T cell activation d An asymmetric intracellular dimer is involved in HMBPPmediated gd T cell activation d HMBPP doubles the binding force between extracellular BTN3A and Vg9Vd2 TCR SUMMARYHuman Vg9Vd2 T cells respond to microbial infections and malignancy by sensing diphosphate-containing metabolites called phosphoantigens, which bind to the intracellular domain of butyrophilin 3A1, triggering extracellular interactions with the Vg9Vd2 T cell receptor (TCR). Here, we examined the molecular basis of this ''inside-out'' triggering mechanism. Crystal structures of intracellular butyrophilin 3A proteins alone or in complex with the potent microbial phosphoantigen HMBPP or a synthetic analog revealed key features of phosphoantigens and butyrophilins required for gd T cell activation. Analyses with chemical probes and molecular dynamic simulations demonstrated that dimerized intracellular proteins cooperate in sensing HMBPP to enhance the efficiency of gd T cell activation. HMBPP binding to butyrophilin doubled the binding force between a gd T cell and a target cell during ''outside'' signaling, as measured by single-cell force microscopy. Our findings provide insight into the ''inside-out'' triggering of Vg9Vd2 T cell activation by phosphoantigen-bound butyrophilin, facilitating immunotherapeutic drug design.

Hepatitis B virus (HBV)-encoded X antigen (HBxAg) contributes to the development of hepatocellular carcinoma (HCC). A frequent characteristic of HCC is reduced or absent expression of the cell adhesion protein, Ecadherin, although it is not known whether HBxAg plays a role. To address this, the levels of E-cadherin were determined in HBxAg-positive and -negative HepG2 cells in culture, and in tumor and surrounding nontumor liver from a panel of HBV carriers. The results showed an inverse relationship between HBxAg and E-cadherin expression both in tissue culture and in vivo. In HBxAgpositive cells, E-cadherin was suppressed at both the mRNA and protein levels. This was associated with hypermethylation of the E-cadherin promoter. Depressed E-cadherin correlated with HBxAg trans-activation function, as did the migration of HepG2 cells in vitro. Decreased expression of E-cadherin was also associated with the accumulation of b-catenin in the cytoplasm and/ or nuclei in tissues and cell lines, which is characteristic of activated b-catenin. Additional work showed that HBxAg-activated b-catenin. Together, these results suggest that the HBxAg is associated with decreased expression of E-cadherin, accumulation of b-catenin in the cytoplasm and nucleus, and increased cell migration, which may contribute importantly to hepatocarcinogenesis.

The removal of the entire osseous compartment either by en bloc or piecemeal method in combination with the long-term use of bisphosphonate could significantly reduce the recurrence rate of GCT of the mobile spine. Age less than 40 years is a favorable prognostic factor for GCT in the mobile spine.