Hypoxia Factors Contribute to Maintenance of Regulatory T-cell Function

A team of cell biologists has identified a molecular pathway that maintains the stability and function of regulatory T-cells (Treg cells), which are components of the immune system that suppress immune responses of other cells and act as an important “self-check” built into the immune system to prevent excessive reactions.

Foxp3+ regulatory Treg cells play a critical role in immune homeostasis; however, the mechanisms to maintain their function have not been clarified. In this regard, investigators at the La Jolla Institute for Allergy and Immunology (CA, USA) worked with a genetically engineered mouse model to determine how Treg function was maintained.

The mice were engineered to lack the gene that encodes the enzyme von Hippel-Lindau (VHL). Among the activities carried out by VHL is regulating hypoxia-inducible factor 1alpha (HIF-1alpha), an oxygen sensor that controls the expression of various genes for glucose metabolism under conditions of low oxygen levels.

The investigators reported in the June 16, 2015 online edition of the journal Immunity that the amount of HIF-1alpha within Treg cells lacking VHL increased sharply. In addition, the Treg cells became highly activated and produced large amounts of inflammatory cytokines, such as interferon-gamma (INF-gamma). HIF-1alpha knockdown or knockout could reverse the increased IFN-gamma production by VHL-deficient Treg cells and restore their suppressive function in vivo.

“Due to the inhibitory function of Treg cells, people have been trying to use these cells for therapy in human autoimmune diseases or transplantation,” said senior author Dr. Yun Cai Liu, professor of cell biology at the La Jolla Institute for Allergy and Immunology. “Our results suggest that these cells may not be stable, and, under certain conditions, may be even converted into inflammatory cells. Our studies imply that the change of oxygen levels in different tissues can be sensed by Treg cells and that this process is critically important for maintaining the correct balance between activation and suppression of the immune system.”

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La Jolla Institute for Allergy and Immunology