19 December 2023

PUBLICATION SPOTLIGHT – Are newly identified metabolic regulating molecules promising for T-cell immunotherapy?

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By Shohreh Issazadeh-Navikas, Professor & group leader

How would you summarise your study in one sentence?

Regulation of mitochondria respiration and metabolism, the powerhouse of all cells, is essential for anti-inflammatory FoxA1+ regulatory T cell generation.

Can you describe briefly what you have explored and how?

Previously, we identified a population of anti-inflammatory regulatory T cells called FoxA1+ T regulatory cells, which are generated in inflamed brain and in blood of patients with multiple sclerosis who benefit from treatment with a cytokine called interferon beta. Here we generated a new model and used human healthy blood to investigate how these anti-inflammatory cells can be generated because they have potential for many inflammatory diseases as a future therapy. We found that although mitochondria are central for the well-being of all cells, how the mitochondria are being regulated is a central event for identity and function of these specialized regulatory T cells. Moreover, we identified a new previously unknown molecule, PRAKG2.2, which plays a central role for generation of these cells via regulating mitochondrial respiration and metabolism. If we engineer usual T cells from blood to highly express this new molecule, this is sufficient for usual T cells to become anti-inflammatory regulatory T cells and prevent harmful disease promoting cells.

What would you say is the novelty in this study?

The novelty is the identification of a small molecule which if introduced in cells can generate anti-inflammatory T cells that are important in combating inflammatory diseases of central nervous system like MS. Furthermore, these cells are potential therapeutic target in many other autoimmune and inflammatory diseases such as type I diabetes, inflammatory bowel disease, rheumatoid arthritis etc.

How do the results relate to the scientific field with respect to what is already known?

The distinct nature of FoxA1+ Tregs compared to the previously known FoxP3+ Tregs is the fact that mitochondrial functions via regulation of this newly identified molecules is pivotal for identity and stability of this anti-inflammatory Treg cells. Although there are several companies intending to create new therapeutic ways to generate or increase FoxP3+Tregs for treating autoimmune and inflammatory diseases, these cells might change character in inflammatory organs, but FoxA1+Tregs are less plastic after generation therefore a potential stable treatment option.

Can you describe the potential of the findings beyond the research field?

These discoveries hold the potential to redefine our comprehension of FoxA1 Treg generation and could provide valuable insights for using these findings offering potential future treatments for autoimmune diseases. Moreover, a deeper understanding of the molecular mechanisms at play in these cells could unveil promising new therapeutic targets for autoimmune diseases.

What are the next stages in this research?

Our commitment involves an in-depth exploration of the nature of FoxA1 Tregs in other autoimmune conditions like type I diabetes, inflammatory bowel disease, etc. aiming to gain a deeper understanding and characterization of this population. This exploration is crucial for the identification of potential targets to generate FoxA1+ Tregs for treatment of inflammatory and autoimmune diseases.

Read full study in Science Advances: PRKAG2.2 is essential for FoxA1+ regulatory T cell differentiation and metabolic rewiring distinct from FoxP3+ regulatory T cells