Metabolism determines how regulatory T cells, the immune regulators that keep inflammation in check, are activated. Recent work by scientists at St. Jude Children’s Research Hospital uncovered how the cell’s energy powerhouses—mitochondria—and recycling organelles—lysosomes—collaborate to turn these cells on and off. The findings, which could help explain autoimmune and inflammatory conditions and refine cancer immunotherapy, appear today in Science Immunology.
When the immune system spots a threat, it triggers inflammation. Regulatory T cells also become active, ensuring that the inflammation resolves neatly. These cells are so vital that the 2025 Nobel Prize in Physiology or Medicine honored their discovery.
If regulatory T cells fail, people can suffer from tissue damage, over‑active inflammation, or autoimmune disorders. Yet the exact molecular pathways that launch these cells remained unclear, limiting therapeutic options for these diseases.
“We identified how regulatory T cells switch on and become more suppressive during inflammation,” explained corresponding author Hongbo Chi, Ph.D., chair of the Immunology Department and co‑director of the Center of Excellence for Pediatric Immuno‑Oncology. “Mapping the metabolic rewiring through their activation cycles gives us a roadmap for future therapies and for improving current immune‑based treatments.”
Researchers used single‑cell RNA sequencing on mouse inflammatory models to trace how gene expression linked to energy metabolism shifts in regulatory T cells. They identified four distinct metabolic states as the cells progressed through activation.
“The cells start in a low‑activity, quiescent metabolic mode, then step up to intermediate activation, eventually reaching a highly metabolically active state before returning to baseline,” said first author Jordy Saravia, Ph.D., from the St. Jude Immunology Division. “The final population that re‑enters quiescence was a new observation that may explain how these suppressor cells shut down after their job is done.”
To uncover what drives these state transitions, the team examined cellular structure with electron microscopy. They found that more‑activated cells harbored more mitochondria, and those mitochondria displayed denser cristae—folds that increase power generation—indicating a vital role for mitochondrial structure in activation.
When the scientists removed the gene Opa1, essential for shaping mitochondrial cristae, the cells compensated by boosting lysosome numbers. Yet regulatory T cells lacking Opa1 still could not meet energy demands or retain suppressive function.
Deleting another key gene, Flcn, which limits lysosome activity, also impaired these cells. Further work revealed that loss of either Flcn or Opa1 altered TFEB, a regulator of lysosome‑associated genes, through enhanced AMPK signaling—linking mitochondrial and lysosomal communication.
“Our study is the first to chart inter‑organelle signaling between mitochondria and lysosomes in regulatory T cells,” Saravia noted. “These pathways govern distinct activation stages and ultimately dictate the cells’ suppressive efficiency.”
Interestingly, absence of Flcn prevented regulatory T cells from up‑regulating genes that allow them to infiltrate non‑lymphoid tissues like lung and liver—sites also targeted by regulatory T cells in tumors. The team tested whether disrupting Flcn could boost anti‑tumor immunity.
Removing Flcn in regulatory T cells led to stronger immune responses against tumors and smaller tumor sizes. It also reduced the build‑up of exhausted CD8⁺ T cells, which can hinder immunotherapy efficacy.
“We have now an unbiased view of the metabolic mechanics that activate regulatory T cells during inflammation,” Chi concluded. “Understanding how organelles steer the cells between rest and activation opens fresh opportunities to treat autoimmune conditions and enhance cancer therapies.”