Metabolic Control of Regulatory T Cells Reveals Key to Therapeutic Interventions

Scientists at St. Jude Children's Research Hospital have made a groundbreaking discovery in understanding the metabolic control of regulatory T cells, the immune cells that prevent inappropriate immune system activation. The researchers found that mitochondria, the powerhouse of cells, and lysosomes, cellular recycling systems, work together to activate and deactivate these immune controllers. This study has significant implications for understanding autoimmune and inflammatory diseases, as well as improving immunotherapy for cancer.

Key Takeaways:

• Scientists at St. Jude Children's Research Hospital discovered that mitochondria and lysosomes play a crucial role in regulating the activation states of regulatory T cells.
• The researchers found that mitochondria increase in number and density as cells become more activated, and deleting genes critical for mitochondrial and lysosomal function impairs regulatory T cell function and energy production.
• The study uncovered four unique 'states' that emerged from analyzing gene expression related to energy production and cellular metabolism in regulatory T cells.
• The researchers discovered that deleting the gene Opa1, which is necessary for mitochondria to alter their cristae, led to regulatory T cells failing to generate sufficient energy or maintain their immunosuppressive function.
• Deleting the gene Flcn, which is critical for restraining lysosomes, also led to regulatory T cells becoming defective, and Flcn deletion in regulatory T cells may improve anti-tumor immunity and benefit cancer immunotherapies.
• The study revealed that inter-communication between mitochondria and lysosomes in regulatory T cells controls discrete activation states and ultimately, how well these cells perform their immunosuppressive functions.

Statistics:

• The researchers found that regulatory T cells undergo dynamic metabolic changes, starting out in a relatively 'quiescent' or relatively inactive metabolic state, then transitioning to an intermediately activated and then a highly metabolically activated state, before returning to a baseline status.
• Mitochondrial cristae density increased as regulatory T cells became more activated, with increases in cristae density correlating with increased regulatory T cell activation.
• Regulatory T cells without Opa1 or Flcn failed to generate sufficient energy or maintain their immunosuppressive function, and their function was partially restored by increasing the abundance of lysosomes.
• Flcn deletion in regulatory T cells reduced the accumulation of exhausted CD8+ T cells, a subset of cells that can impede responses to immunotherapies in tumors.

Sources:

• St Jude Childrens Research Hospital
• Science Immunology
• National Institutes of Health grants (R01CA253188, R01AI105887, R01AI131703, R01AI140761, R01AI150241, R01AI150514, and P30CA021765)
• American Lebanese Syrian Associated Charities (ALSAC)
• St Jude Children's Research Hospital website (stjude.org)