Using a systems biology approach, researchers from St. Jude Children’s Hospital have discovered how the Hippo pathway kinases Mst1 and Mst2 work together to regulate the function of different dendritic cell types. Details on their research were published today in Nature.
"Dendritic cells are crucial for activating the adaptive immune response, including priming anti-tumor T cells," said Hongbo Chi, Ph.D., a member of the St. Jude Department of Immunology. "But regulation of the distinct functions of different dendritic cell subsets have been poorly understood. We wanted to change that.
"These findings provide clues for new treatment strategies for cancer or immune disorders by modulating the activity of dendritic cells to shape the immune response," said Chi, who is co-corresponding author of the research with Jiyang Yu, Ph.D., an assistant member of the St. Jude department of computational biology. Xingrong Du, Ph.D., a postdoctoral fellow in Chi's laboratory, is the first author.
Yu and his colleagues developed the systems biology algorithm, which is called NetBID, short for data-driven network-based Bayesian inference of drivers.
Researchers used NetBID to analyze differences in networks of the different dendritic cell subtypes. Mst1/2 and the Hippo signaling pathway emerged as a key regulator of dendritic cell function and the T cell response.
This study focused on dendritic cell subsets that have distinct effects on the immune system. One, CD8α+ dendritic cells, primes production of CD8 T cells central to fighting tumors and infections. The other, CD8α- dendritic cells, primes production of a different T cell subtype.
Researchers compared metabolic activity in the different dendritic cells and found that the CD8α+ dendritic cells were more metabolically active than CD8α- dendritic cells. They reached that conclusion by comparing oxygen metabolism in the cells' power plants, mitochondria. Investigators also showed that manipulating metabolism affected CD8α+ dendritic cell function and T cell priming.
"While metabolism is known to be important generally in the immune response, this study defines, we believe for the first time, that not only is it important in dendritic cell function, but that the two dendritic cell subsets have distinct metabolism controlled by Hippo signaling," Chi said. "In addition, we showed that manipulating metabolism directly affects function of the dendritic cell subset."