(MEMPHIS, Tenn. \u2013 October 24, 2025) Metabolism guides the activation states of regulatory T cells, the immune cells that prevent inappropriate activation of the immune system. St. Jude Children\u2019s Research Hospital scientists recently uncovered how mitochondria, the powerhouse of cells, and lysosomes, cellular recycling systems, work together to activate and deactivate these immune controllers. Their discoveries carry implications from understanding autoimmune and inflammatory diseases to improving immunotherapy for cancer. The findings were published today in Science Immunology.<\/p>\n
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When the immune system identifies and responds to a threat, it creates inflammation to combat the problem. A subset of immune cells, called regulatory T cells, also become activated and ensure that the inflammation is properly controlled. They return 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.<\/p>\n
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When regulatory T cells don\u2019t function properly, people can develop tissue damage from uncontrolled inflammation or autoimmune disorders due to the immune system being inappropriately activated. Despite their importance, the precise molecular process driving regulatory T cell activation has been unclear. This limits the capacity to harness these cells to treat autoimmune or inflammatory disorders.<\/p>\n
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\u201cWe discovered how regulatory T cells are activated and become more immunosuppressive during inflammation,\u201d said corresponding author Hongbo Chi<\/a>, PhD, Department of Immunology<\/a>\u00a0chair and Center of Excellence for Pediatric Immuno-Oncology<\/a>\u00a0(CEPIO) co-director. \u201cBy 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.\u201d<\/p>\n \u00a0<\/p>\n The scientists uncovered a link between metabolism and signaling and regulatory T-cell activation by performing single-cell RNA sequencing of these T cells in a mouse model of inflammation. They noted four unique \u2018states\u2019 that emerged from analyzing gene expression related to energy production and cellular metabolism.<\/p>\n \u00a0<\/p>\n \u201cWe saw that these regulatory T cells undergo dynamic metabolic changes, starting out in a relatively \u2018quiescent\u2019 or relatively inactive metabolic state, then transition to an intermediately activated and then a highly metabolically activated state, before returning to a baseline status,\u201d said first author Jordy Saravia, PhD, St. Jude Department of Immunology. \u201cThat final subset, which re-enters metabolic quiescence, has never been described for regulatory T cells, but may explain how these immune suppressors are \u2018turned off\u2019 when their task is done.\u201d<\/p>\n \u00a0<\/p>\n A tale of two organelles: mitochondria and lysosomes<\/p>\n \u00a0<\/p>\n After discovering the different regulatory T cell activation states, the researchers wanted to know the mechanisms controlling these transitions. Using electron microscopy, they found that the more activated cell states contained more mitochondria than the resting cell states. Additionally, mitochondria from the more activated states contained more dense cristae, or \u201cfolds\u201d, like having more generators in each power plant, suggesting that this mechanism is an important part of regulatory T cell activation during inflammation.<\/p>\n \u00a0<\/p>\n Interestingly, when the scientists deleted Opa1, a gene needed for mitochondria to alter their cristae, they saw that the cells partially compensated by increasing the abundance of lysosomes. Lysosomes recycle materials from the inside of cells, which can then be used to make energy or other building blocks. However, regulatory T cells without Opa1 still failed to generate sufficient energy or maintain their immunosuppressive function.<\/p>\n \u00a0<\/p>\n When the researchers instead deleted a gene critical for restraining lysosomes, Flcn, regulatory T cells again became defective. Through additional experiments, they uncovered that deletion of either Flcn or Opa1 altered the activity of TFEB, a protein that controls lysosome-associated gene expression as part of an energy stress-response pathway. They further demonstrated that this link between mitochondrial dysfunction and increased TFEB activity was due to enhancing signaling of another major pathway, AMPK signaling, presenting further evidence of intercommunication between the two organelles.<\/p>\n \u00a0<\/p>\n \u201cWe are the first to dissect this inter-organelle signaling between mitochondria and lysosomes in regulatory T cells,\u201d Saravia said. \u201cIt shows that these metabolic signaling pathways control discrete activation states, and ultimately, how well these cells perform their immunosuppressive functions.\u201d<\/p>\n \u00a0<\/p>\n Altering regulatory T cells may improve future therapies<\/p>\n \u00a0<\/p>\n One of the researchers\u2019 surprising findings is that without Flcn, regulatory T cells are unable to upregulate gene expression programs that let them gather in non-lymphoid tissues such as the lung and liver. Those same programs are also associated with regulatory T-cell function in tumors, which suppress the activity of anti-tumor immune cells. The researchers tested if Flcn deletion in regulatory T cells could help anti-tumor immune cells to better control tumor growth.<\/p>\n \u00a0<\/p>\n They found that this gene deletion enabled more effective immune responses against tumors, leading to decreased tumor size. Notably, Flcn deletion in regulatory T cells also reduced the accumulation of exhausted CD8+ T cells, a subset of cells that can impede responses to immunotherapies in tumors. These findings suggest that altering Flcn activity in regulatory T cells may open a new avenue to improve anti-tumor immunity and benefit cancer immunotherapies.<\/p>\n \u00a0<\/p>\n \u201cWe\u2019ve taken the first unbiased look at the metabolic mechanisms of how regulatory T cells become activated during inflammation,\u201d Chi said. \u201cWe now have a better understanding of how organelles direct resting versus highly activated regulatory T-cell states in inflammation and tissues, providing new insights that will help improve treatments for autoimmune disorders and cancer.\u201d<\/p>\n \u00a0<\/p>\n Authors and funding<\/p>\n The study\u2019s other authors are Nicole Chapman, Xiaoxi Meng, Cliff Guy, Hao Shi, Yogesh Dhungana, Jia Li, Zhiyuan You, Anil KC, Jana Raynor, Erienne Norton, Sarah La Grange, Camenzind Robinson and Peter Vogel, all of St. Jude, and Yu Sun, Isabel Risch, Wei Li, Haoran Hu, Seon Ah Lim and Sharad Shrestha, all formerly of St. Jude.<\/p>\n \u00a0<\/p>\n The study was supported by grants from the National Institutes of Health grants (R01CA253188,<\/p>\n R01AI105887, R01AI131703, R01AI140761, R01AI150241, R01AI150514 and P30CA021765) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.<\/p>\n St. Jude Media Relations Contacts<\/p>\n Michael Sheffield Desk: (901) 595-0221 Cell: (901) 379-6072 michael.sheffield@stjude.org<\/a> media@stjude.org<\/a><\/p>\n \u00a0<\/p>\n St. Jude\u00a0Children’s Research Hospital<\/p>\n St. Jude\u00a0Children\u2019s Research Hospital is leading the way the world understands, treats, and cures childhood catastrophic diseases. As the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children,\u00a0St. Jude\u00a0advances groundbreaking research and shares its discoveries worldwide to accelerate progress in pediatric medicine. Treatments developed at\u00a0St. Jude\u00a0have helped increase overall childhood cancer survival rates from 20% to 80% since the hospital opened more than 60 years ago. Through collaboration and innovation,\u00a0St. Jude\u00a0is working to ensure that children everywhere have access to the best possible care.\u00a0To learn more, visit\u00a0stjude.org<\/a>,\u00a0read\u00a0St. Jude\u00a0Progress,\u00a0a digital magazine<\/a>,\u00a0and follow\u00a0St. Jude\u00a0on social media at\u00a0@stjuderesearch<\/a>.<\/p>\n \t\t\t\t\t\t\t\t\t\t