Francisco Quintana, PhD

Francisco Quintana

Francisco Quintana, PhD, of the Ann Romney Center for Neurologic Diseases, and colleagues have identified metabolic pathways that regulate a population of T cells that help control immune responses and play a role in autoimmune diseases such as multiple sclerosis. The research team finds that type 1 regulatory T cells (Tr1 cells) are controlled in part by two transcription factors, which may in turn be influenced by a person’s diet and gut microbes. The new work, published in Nature Medicine, points to potential therapeutic targets for immune-related disorders.

Recent studies have suggested that T cell fate hinges upon metabolic reprogramming – or a shift in the levels of nutrients and oxygen available in the cell’s environment. During an immune response, metabolites in the environment and the bioenergetic needs of T cells may shift. In the new study, the research team uncovers potential mechanisms by which changes in metabolite levels at sites of inflammation may influence the production of Tr1 cells. They find that cross-talk between two transcription factors, hypoxia inducible factor-1 alpha (HIF1-alpha) and aryl hydrocarbon receptor (AHR), may help control the immune system’s response to signals from the cellular environment.

The researchers find that early in metabolic reprogramming, HIF1-alpha drives Tr1 cell differentiation. At later time points, AHR takes over the control of Tr1 cell differentiation, and degrades HIF1-alpha. At sites of inflammation, where oxygen levels drop and extracellular ATP levels rise, AHR may become inactivated, stopping Tr1 cell differentiation. Environmental factors upstream of AHR, such a person’s diet or the makeup of the microorganisms living in a person’s gut, may also influence this pathway.

“These results suggest that HIF1-alpha and AHR integrate immunological, metabolic and environmental signals to regulate the immune response,” the authors write. “Our findings identify metabolic pathways that regulate the differentiation of Tr1 cells and provide potential targets for their therapeutic modulation in immune-mediated disorders.”