Metabolic Signaling Mechanisms that Regulate eTreg Cell Function Uncovered

Researchers from St. Jude Children's Research Hospital report that they have revealed the metabolic signaling mechanisms that regulate the function of effector regulatory T cells (eT_reg cells).

"This process is quite fascinating to us, and helps explain how metabolites can drive selective signaling pathways to enforce the differentiation, persistence and function of eT_reg cells," said Hongbo Chi, Ph.D., corresponding author of the paper published in Cell Metabolism today. "We were looking specifically at suppression of autoimmunity that can develop spontaneously in our models, but we also know T_reg cells play a role in multiple diseases."

The team found that isoprenoids are essential for the suppressive activity of activated T_reg cells such as eT_reg cells. Isoprenoids are also required for cellular processes like post-translational lipid modifications, specifically protein farnesylation and geranylgeranylation. These processes are mediated by Fntb and Pggt1b, respectively. Disruption of these processes by T_reg cell-specific deletion of Fntb or Pggt1b causes mice to develop autoimmunity.

Further research into the metabolic signaling mechanisms revealed the discrete details of T_reg cell-mediated immune suppression downstream of T cell receptor signaling. Fntb acts through two parallel pathways to promote eT_reg cell persistence: the protein kinase mTORC1, which regulates metabolic reprogramming of T_reg cells, and the immune receptor ICOS. Pggt1b enforces signaling through the small G protein Rac to support eT_reg cell differentiation.

"We were able to dissect how metabolic regulation controls eT_reg cell differentiation and maintenance," said first author Wei Su. "This bidirectional interplay between intracellular signaling and metabolism allows eT_reg cells to maintain the self-tolerance in our body."