Protein complex that shapes T cells' destiny identified
Scientists at a US-based hospital have identified the mechanism that determines how T cells specialise their development.
Corresponding author Hongbo Chi, PhD, and colleagues from St. Jude Children’s Research Hospital have reported the protein complex mTORC1 serves as a bridge between environmental signals and metabolic programs to influence the fate of developing T cells.
The immunologists discovered that mTORC1 acts in response to cues from in and around developing T cells and intersects with metabolic activity to influence whether the cells become conventional or unconventional T cells. To their surprise, researchers found that disrupting mTORC1 led to metabolic changes that favoured development of unconventional T cells at the expense of conventional T cells.
“We know that conventional and unconventional T cells are fundamentally different,” said Hongbo Chi, PhD, a member of the St. Jude Department of Immunology faculty. “They express different cell surface receptors. The cells have different functions. But until now the mechanism that helps decide their fates has remained largely unknown.”
T cells play a central role in the adaptive immune system, functioning like elite commando units trained to find and eliminate specific viruses and other threats.
In humans, the vast majority of T cell receptors have an alpha (α) protein chain and a beta (β) chain. These are conventional T cells that circulate widely and reside in the spleen and lymph nodes. A smaller number of T cells carry receptors made from a gamma (γ) and a delta (δ) protein chain. They belong to the family of unconventional T cells that are found in the gut, skin and other barrier tissues.
Working with mouse models and developing T cells in the laboratory, Chi and his colleagues showed that activation of mTORC1 revs up energy production through glycolysis and oxidation to fuel anabolic metabolism and promote development of αβ T cells.
When investigators disabled mTORC1, metabolism was disrupted, which was associated with a reduction in the αβ T cells and an increase in γδ T cells.
Deleting a key component of mTORC1, a protein called RAPTOR disabled mTORC1 and altered the metabolic balance in developing T cells. The change reduced anabolic metabolism but increased levels of toxic molecules called reactive oxygen species (ROS) and upregulated activity along a molecular pathway that promotes cell growth.
The change enhanced development of γδ T cells in the thymus and hindered development of αβ T cells.
Researchers also reported expression of signature genes associated with γδ T cells was enhanced in mice when RAPTOR was deleted from the mTORC1 complex.
“This research establishes mTORC1-driven metabolic signalling as a decisive factor in determining the fate of developing T cells and suggests metabolic processes are a fundamental mechanism that connects external signals with internal processes to guide the fate of immune cells,” Chi said.
The findings have been published in the journal Science Immunology. The first authors are Daniel Bastardo Blanco and Xiang Chen of St. Jude and Kai Yang, formerly of St. Jude. The other authors are Pradyot Dash, Geoffrey Neale, Celeste Rosencrance, John Easton, Wenan Chen, Changde Cheng, Yogesh Dhungana, Anil KC, Walid Awad, Xi-Zhi Guo and Paul Thomas, all of St. Jude.
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