Scientists research hospital of St. Jude identified a hidden element that affects the production of T-cells that fight cancer and infections. The study appeared in the journal Nature.
Drivers are hidden kinases (enzymes) Mst1 and Mst2. Researchers have shown that Mst1 Mst2 and work together to regulate the function of various types of dendritic cells (subsets). Dendritic cells are key regulators of the adaptive immune system, including T cells, which are central to cancer immunotherapy.
"Dendritic cells are crucial for the activation of the adaptive immune response, including antitumor priming of T-cells," - said Hongbo Chi, Ph.D., a member of the St. Jude Department of Immunology.. "But the regulation of specific functions of the various subsets of dendritic cells has been poorly understood. We wanted to change this.
"These data provide the key to new strategies for treating cancer or immune disorders by modulating the activity of dendritic cells to generate an immune response", - said Chi, who is the co-author of the study with Huyang Yu, assistant chair of Computational Biology St. Jude.. Ksingrong Du, Ph.D., is a doctoral student in the laboratory of Chi, it is the first author.
The adoption of a systems approach
The key role played by the study of systems biology algorithm based on the data referred to NetBID. Yu and his colleagues have developed NetBID.
Yu and his team integrated the gene expression, proteomics and the whole data phosphorylated proteomics lab Chi and other sources for reverse-engineering biological networks in mouse dendritic cells. NetBID researchers used to analyze the differences in networks of various subtypes of dendritic cells. To their surprise, Mst1 / 2 signaling pathway and Hippo emerged as a key regulator of the functions of dendritic cells and T cell response.
"The way Hippo is known that regulates body size of the animals, instead of immune function in dendritic cells," - said Chi. Yu compared Mst1 / 2 with a criminal boss, the role of which is hidden behind several layers of subordinates. "A systematic approach based on the data gave us an opportunity to find hidden drivers underlying the differential functions of subsets of dendritic cells," - said Yu
Ji added that interdisciplinary cooperation is essential for research.
Metabolism and signaling
This study focused on subsets of dendritic cells, which have a definite effect on the immune system. One, CD8α + dendritic cells, production of producing CD8 T cells central to combat tumors and infections. Other CD8α-production of dendritic cells produce other subtypes of T cells.
The researchers compared the metabolic activity in various dendritic cells and found that CD8 + dendritic cells are more metabolically active than CD8-dendritic cells. They came to this conclusion by comparing the oxygen metabolism in the cell power plants, the mitochondria. Researchers have shown that metabolic manipulation affects the function of CD8α + dendritic cells and priming of T cells.
"It is known that the metabolism is known to be important in the immune response in general, this study determines not only what is important for the function of dendritic cells, but also the fact that the two subsets of dendritic cells have a different metabolism, monitored alarm Hippo, - said Chi. "In addition, we have shown that manipulation of metabolism directly affect the function of dendritic cell subsets."
Researchers have shown that Mst1 / 2 plays a key role in signaling of cytokine that is necessary for the priming of T cells and ensure that the immune response. Cytokines are small secreted molecules that modulate the immune response.
The researchers showed that, instead of working through the normal signaling pathways, Mst1 / 2 takes an unconventional path to a simple T-cells. Mst1 / 2 uses the signaling NF-κB, a non-convention way to trigger the production of IL-12 cytokine (IL-12). IL-12 promotes the function of CD8α + dendritic cells and transmits responses to CD8 T cells.
"Research shows that Mst1 / 2 integrates metabolic activity and cytokine signaling, in order to selectively control the function CD8α + dendritic cells," - said Chi.
«NetBID algorithm can be used to search for other datasets for hidden drivers and the study of biological issues," - said Yu. "This algorithm has been used to analyze the differences in the network between the different subtypes of cancer or between drug-resistant and sensitive cancer patients to identify potential biomarkers and therapeutic targets. Key - a data-centric, and context-aware network ", - he said.