The possibility that mycobacterial infections induce variant cytokine mRNA encoding a functionally distinct protein for immune regulation has not been addressed. In this study, we reported that Mycobacterium tuberculosis and bacillus Calmette-Guérin infections of macaques induced expression of variant IL-4 (VIL-4) mRNA encoding a protein comprised of N-terminal 97 aa identical with IL-4, and unique C-terminal 96 aa including a signaling-related proline-rich motif. While VIL-4 could be stably produced as intact protein, the purified VIL-4 induced apparent expansion of phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP)-specific Vγ2Vδ2 T cells in dose- and time-dependent manners. The unique C-terminal 96 aa bearing the proline-rich motif (PPPCPP) of VIL-4 appeared to confer the ability to expand Vγ2Vδ2 T cells, since simultaneously produced IL-4 had only a subtle effect on these γδ T cells. Moreover, VIL-4 seemed to use IL-4R α for signaling and activation, as the VIL-4-induced expansion of Vγ2Vδ2 T cells was blocked by anti-IL-4R α mAb but not anti-IL-4 mAb. Surprisingly, VIL-4-expanded Vγ2Vδ2 T cells after HMBPP stimulation appeared to be heterologous effector cells capable of producing IL-4, IFN-γ, and TNF-α. Thus, mycobacterial infections of macaques induced variant mRNA encoding VIL-4 that functions as growth factor promoting expansion of HMBPP-specific Vγ2Vδ2 T effector cells.
Reconstruction of hepato-biliary networks is very important to maintaining liver organoids in vitro, since the accumulation of bile has been proven to be toxic to hepatocytes, especially in long-term culture. We have developed culture methods for reconstructing bile canaliculi (BC) and bile ducts (BDs) formed by small hepatocytes (SHs) which are hepatic progenitor cells, and biliary epithelial cells (BEes), respectively. To study the mechanism of biliary excretion, we need to establish a co-culture system for SHs and BEes. A limitation of conventional culture methods in investigating the mechanisms of hepato-biliary connections is the difficulty to observe the dynamic interactions between SHs and BEes in culture. In addition, patterned constructs do not form in conventional cultures due to the lack of organization of cells. A system that allows more complex dynamics between SHs and BEes to occur is needed in order to investigate the interactions between these cell types. Here, we present an approach called Microfluidic Hydrostatic Deposition Patterning (MHDP) that patterns SH and BEe colonies with defined shape and position, which promotes productive interactions between the cells and eventually induce the formation of heterogeneous tissues integration which is thought to be a prototype of complete biliary networks.
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