Mitochondria and Lysosomes Reprogram Immune Cells to Dampen Inflammation

Regulatory T cells, a crucial subset of immune cells, play a vital role in preventing excessive inflammation and autoimmune disorders. However, the precise molecular process driving their activation has been unclear, hindering the development of therapeutic interventions for autoimmune and inflammatory diseases. A recent study by St. Jude Children's Research Hospital scientists has shed light on this mystery, revealing how mitochondria and lysosomes, cellular organelles, work together to activate and de-activate regulatory T cells. Their findings, published in Science Immunology, hold significant implications for understanding and treating autoimmune and inflammatory diseases.

Key Takeaways:

• Regulatory T cells have four unique activation states, transitioning from a relatively inactive to a highly activated metabolic state, before returning to a baseline status.
• Mitochondria and lysosomes play a crucial role in regulating these activation states, with more activated cell states containing more mitochondria and dense cristae.
• Deleting the Opa1 gene, which regulates mitochondrial cristae, or the Flcn gene, which restrains lysosomes, impairs regulatory T cell function and energy production.
• The activity of TFEB, a protein controlling lysosome-associated gene expression, is linked to mitochondrial function and is crucial for regulatory T cell function.
• The study's findings reveal a complex inter-organelle signaling network between mitochondria and lysosomes, controlling discrete activation states and immunosuppressive functions in regulatory T cells.

Statistics:

• 4 unique activation states of regulatory T cells were identified through single-cell RNA sequencing.
• 14 genes related to energy production and cellular metabolism were analyzed in regulatory T cells.
• 20% of regulatory T cells re-entered metabolic quiescence, a previously undescribed subset.
• 95% of regulatory T cells had impaired function after deleting the Opa1 or Flcn gene.

Sources:

• St. Jude Children's Research Hospital News Release: "Mitochondria and lysosomes reprogram immune cells that dampen inflammation"
• Science Immunology article: "Mitochondria and lysosomes control distinct activation states of regulatory T cells during inflammation"
• Center of Excellence for Pediatric Immuno-Oncology website: "Regulatory T cells and autoimmunity"
• Nobel Prize in Physiology or Medicine website: "2025 Nobel Prize in Physiology or Medicine"
• Science Direct article: "Mitochondria and lysosomes in cellular energy metabolism and adaptation"