Mitochondria and lysosomes cooperate to control regulatory T cell activation

Metabolism drives the activation states of regulatory T cells, immune cells that prevent inappropriate activation of the immune system. The scientists of the Children’s Research Hospital St. Jude recently revealed how mitochondria, the cell’s powerhouse, and lysosomes, the cell’s recycling systems, work together to turn these immune controllers on and off. Their discoveries have implications from understanding autoimmune and inflammatory diseases to improving cancer immunotherapy. The findings were published today in Science Immunology.

When the immune system recognizes and responds to a threat, it creates inflammation to fight the problem. A subset of immune cells, called regulatory T cells, are also activated and ensure that inflammation is properly controlled. They restore a tissue to normal once the threat is neutralized. Regulatory T cells play such an important role that the 2025 Nobel Prize in Physiology or Medicine was awarded in recognition of their original discovery.

When regulatory T cells don’t work properly, people can develop tissue damage from uncontrolled inflammation or autoimmune disorders due to inappropriate activation of the immune system. Despite their importance, the exact molecular process that drives regulatory T cell activation is not clear. This limits the ability to harness these cells to treat autoimmune or inflammatory disorders.

We discovered how regulatory T cells are activated and become more immunosuppressive during inflammation. By defining how cellular metabolism rewires regulatory T cells through different activation states, including their return to quiescence, we provide a roadmap to explore future therapeutic interventions or ways to improve existing immune-related therapies.”

Hongbo Chi, PhD, corresponding author, Chair of the Department of Immunology and Co-Director of the Center of Excellence for Pediatric Immuno-Oncology (CEPIO)

The scientists uncovered a link between metabolism and regulatory T-cell signaling and activation by sequencing single-cell RNA of these T cells in a mouse model of inflammation. They noted four unique “states” that emerged from the analysis of gene expression related to energy production and cellular metabolism.

“We saw that these regulatory T cells undergo dynamic metabolic changes, starting in a relatively ‘quiet’ or metabolically inactive state, then transitioning to an intermediately activated state, then to a highly metabolically activated state, before returning to their original state,” said first author Jordy Saravia, PhD, St. Jude Department of Immunology. “This latter subset, which re-enters metabolic quiescence, has never been described for regulatory T cells, but may explain how these immunosuppressors are ‘turned off’ when their work is done.”

A tale of two organelles: mitochondria and lysosomes

After discovering the different regulatory states of T cell activation, the researchers wanted to learn the mechanisms that control these transitions. Using electron microscopy, they found that the most activated cell states contained more mitochondria than the resting cell states. Additionally, mitochondria from the most activated states contained denser cristae, or “facets,” such as having more generators in each power unit, suggesting that this mechanism is an important part of regulatory T cell activation during inflammation.

Interestingly, when scientists deleted Grandpa1a gene required for mitochondria to change their cristae, they saw that the cells partially compensated by increasing the abundance of lysosomes. Lysosomes recycle materials from inside cells, which can then be used to produce energy or other building blocks. However, regulatory T cells without Grandpa1 however, they failed to produce sufficient energy or maintain their immunosuppressive function.

When the researchers deleted a gene critical for limiting lysosomes, flcnthe regulatory T cells became defective again. Through additional experiments, they revealed this deletion of the two flcn or Grandpa1 altered the activity of TFEB, a protein that controls lysosome-associated gene expression as part of an energy stress response pathway. They further showed that this relationship between mitochondrial dysfunction and increased TFEB activity was due to enhanced signaling of another major pathway, AMPK signaling, showing further evidence of crosstalk between the two organelles.

“We are the first to dissect this intracellular signal between mitochondria and lysosomes in regulatory T cells,” Saravia said. “It shows that these metabolic signaling pathways control distinct activation states and, ultimately, how well these cells perform their immunosuppressive functions.”

Altering regulatory T cells may improve future treatments

One of the surprising findings of the researchers is that without flcnregulatory T cells are unable to upregulate gene expression programs that let them concentrate in nonlymphatic tissues such as the lung and liver. These same programs are also associated with the regulatory function of T-cells in tumors, which suppress the activity of anti-tumor immune cells. The researchers examined whether flcn Deletion in regulatory T cells could help anti-tumor immune cells better control tumor growth.

They found that this gene deletion enabled more effective immune responses against tumors, leading to a reduction in tumor size. particularly, flcn Deletion in regulatory T cells also reduced the accumulation of depleted CD8⁺ T cells, a subset of cells that can block responses to immunotherapies in tumors. These findings suggest that altering Flcn activity in regulatory T cells may open a new avenue for improving antitumor immunity and the benefit of cancer immunotherapies.

“We have taken the first unbiased look at the metabolic mechanisms of how regulatory T cells are activated during inflammation,” Chi said. “We now have a better understanding of how organelles direct resting versus highly activated T-cell regulatory states in inflammation and tissues, providing new insights that will help improve treatments for autoimmune disorders and cancer.”