When the immune system responds to infection or injury, inflammation acts as a defense mechanism—but that same response must be tightly controlled. Regulatory T cells, or Tregs, are the immune system’s internal “braking” mechanism, turning off inflammation when the threat is neutralized.
In new work from St. Jude Children’s Research Hospital published in Science Immunology, scientists describe how Treg cells use internal metabolic signaling to decide when to act and when to rest. “We discovered how regulatory T cells are activated and become more immunosuppressive during inflammation,” said corresponding author Hongbo Chi, PhD, chair of Immunology and co-director of the Center of Excellence for Pediatric Immuno-Oncology (CEPIO).
“By defining how cellular metabolism rewires regulatory T cells through different states of activation, including their return to a resting state, we have provided a roadmap to explore future therapeutic interventions or ways to improve existing immune-related treatments.”
Mapping the four metabolic states of Tregs
Using single-cell RNA sequencing, Chi’s team profiled regulatory T cells under inflammatory conditions and uncovered four distinct activation states driven by shifts in cellular metabolism. As first author Jordy Saravia, PhD, explained, “We saw that these regulatory T cells undergo dynamic metabolic changes, starting out in a relatively ‘quiescent’ or relatively inactive metabolic state, then transition to an intermediately activated and then a highly metabolically activated state, before returning to a baseline status.”
The researchers found that these transitions are powered by mitochondrial remodeling and lysosomal signaling. During inflammation, Tregs expand their mitochondria and increase crista density—microscopic folds that boost energy production. Mitochondrial stress activates the AMPK–TFEB pathway, which triggers lysosomal biogenesis and reprograms the cell’s metabolism. This inter-organelle communication ensures that Tregs can suppress inflammation efficiently and later return to quiescence.
Two key regulators: Opa1 and Flcn
Deleting Opa1, a mitochondrial protein required for maintaining crista structure, caused severe inflammation and loss of immune control in mice. Opa1-deficient Tregs showed energy stress, overactive AMPK signaling, and excessive lysosome production—demonstrating that mitochondrial integrity is essential for suppressive function.
The lysosomal side of the equation involved Flcn (folliculin), which restrains the transcription factor TFEB. Without Flcn, TFEB became hyperactive, pushing Tregs prematurely back into a quiescent state and impairing their ability to accumulate in tissues. The researchers confirmed that this Flcn–TFEB axis is vital for maintaining immune tolerance: mice lacking Flcn in Tregs developed fatal inflammation, which was rescued by deleting TFEB.
From inflammation control to cancer therapy
The study also connects this fundamental biology to cancer. Tregs that infiltrate tumors suppress anti-tumor immunity, helping cancers evade immune attack. When the researchers deleted Flcn specifically in Tregs, they observed reduced tumor growth and more active CD8⁺ T cells, suggesting that tuning Treg metabolism could strengthen immunotherapy responses.
Saravia summarized the broader impact: “We are the first to dissect this inter-organelle signaling between mitochondria and lysosomes in regulatory T cells. It shows that these metabolic signaling pathways control discrete activation states, and ultimately, how well these cells perform their immunosuppressive functions.”
This work reveals a new layer of immune regulation—one governed by metabolism rather than signaling molecules alone. By linking mitochondrial and lysosomal communication to immune tolerance, the St. Jude team has provided new targets for precision immunomodulation. Therapies that restore or inhibit specific metabolic programs in Tregs could one day treat autoimmune disease, chronic inflammation, or cancer, depending on whether the goal is to enhance or release the immune system’s brakes.
