Bim regulates the survival and suppressive capability of CD8+ FOXP3+ regulatory T cells during murine GVHD

peer reviewedCD8+ Foxp3+ T cells (Tregs) are a potent regulatory population whose functional and ontological similarities to CD4+ Fox3+ T cells have not been well delineated. Using an experimental model of graft-versus-host disease (GVHD), we observed that CD8+ Tregs were significantly less potent than CD4+ Tregs for the suppression of GVHD. To define the mechanistic basis for this observation, we examined the T-cell repertoire and the transcriptional profile of in vivo-derived CD4+ and CD8+ Tregs that emerged early during this disease. Polyclonal and alloantigen-induced CD8+ Tregs had repertoire diversity that was similar to that of conventional CD8+ T cells, indicating that a restricted repertoire was not the proximate cause of decreased suppression. Transcriptional profiling revealed that CD8+ Tregs possessed a canonical Treg transcriptional signature that was similar to that observed in CD4+ Tregs, yet distinct from conventional CD8+ T cells. Pathway analysis, however, demonstrated that CD8+ Tregs had differential gene expression in pathways involved in cell death and survival. This was further confirmed by detailed mRNA sequence analysis and protein expression studies, which demonstrated that CD8+ Tregs had increased expression of Bim and reduced expression of Mcl-1. Transplantation with CD8+ Foxp3+ Bim-/- Tregs resulted in prolonged Treg survival and reduced GVHD lethality compared with wild-type CD8+ Tregs, providing functional confirmation that increased expression of Bim was responsible for reduced in vivo efficacy. Thus, Bim regulates the survival and suppressive capability of CD8+ Tregs, which may have implications for their use in regulatory T-cell therapy

Coupled finite-volume/finite-element modelling of the straight-tube Coriolis flowmeter

A coupled finite-volume (FV)/finite-element (FE) numerical model of the straight-tube Coriolis flowmeter is considered. It uses the staggered partitioned algorithm with additional pressure predictor and interfield iterations to minimize the time lag in the fluid-structure coupling procedure.The solutions were evaluated in terms of the fundamental natural frequency of the vibrating system and the corresponding phase difference between the motion of the symmetrically located sensing points on the measuring tube, which are actually exploited as the measuring effects of the Coriolis flowmeter for the fluid density and the mass flowrate, respectively. The FV/FE numerical model was validated by comparison with the solutions of the Euler beam and one-dimensional flow model, as well as with the solutions of the Flügge shell and potential flow model. The respective simulations were performed for different lengths of the measuring tube