by Melissa Rohman, Northwestern University

Graphical abstract. Credit: Immunity (2024). DOI: 10.1016/j.immuni.2024.08.008

Northwestern Medicine scientists have discovered a new mechanism that controls a specialized group of T-cells, known as regulatory T-cells, and may serve as potential therapeutic targets to treat inflammatory disorders and cancer, according to a recent study published in the journal Immunity.

Regulatory T-cells, or Tregs, are a small subset of T-cells that help regulate the immune system and prevent overreactions to antigens. Despite their scarcity, Tregs play an essential role in controlling the body's immune response.

Lymphocyte activation gene 3 (Lag3) is a protein expressed on various T-cell subsets, including Tregs, and has been previously suggested to be important in regulating the functions of Tregs. However, the underlying mechanisms of Treg regulation have remained poorly understood, said Booki Min, Ph.D., professor of Microbiology-Immunology and senior author of the study.

"It is important to keep Treg cell function in check because they tend to lose their regulatory capacity under chronic severe inflammatory conditions. If a patient's Treg cell function is compromised or defective, their immune system can become excessively activated, leading to systemic autoimmune inflammation," said Min, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

In the current study, Min's team used newly developed mouse models where only Tregs lack Lag3 expression, as well as flow cytometry and RNA-sequencing techniques to study the precise role of Lag3 in Treg function.

Using these techniques, the investigators discovered that Lag3 expression is required for Tregs to control autoimmune inflammation in the central nervous system. They also identified that these Lag3-mutant Treg cells express high levels of genes associated with metabolic processes, most notably an increase in the expression of Myc oncogene, which encode transcription factors that regulate cellular metabolism.

In Lag3-mutated Tregs, the scientists found that increased expression of Myc and downstream pathways, including the PI3K-Akt-Rictor pathway, led to diminished Treg function. Furthermore, reversing these processes completely restored Treg cell function, allowing them to control autoimmune inflammation, according to Min.

"What we found was quite unexpected," Min said. "Because the Lag3 mutation completely reprograms Tregs' metabolic processes, causing them to become more glycolytic rather than utilizing oxidative phosphorylation for energy.

"This shows that Lag3 helps Treg cells use oxidative phosphorylation as an energy source. Without Lag3, the Treg cells are confused and start generating energy through glycolysis, which is a less efficient process. As a result, their suppressive functions become less effective at resolving inflammation."

The findings demonstrate a previously unknown role of Lag3 in regulating Tregs' suppressive functions through limiting Myc expression and cellular metabolism. According to Min, these findings could lead to the development of future therapies for different autoimmune diseases and cancer by targeting the Lag3-Myc pathways.

"Targeting Lag3 is a balance. On one hand, we have to boost their function, and on the other hand, we have to lower their function depending on the disease or cancer. In cancer, you have to target Lag3 in Tregs to dampen Treg cell function so that anti-tumor immune cells can be expanded and do their job," Min said.

More information: Dongkyun Kim et al, Inhibitory co-receptor Lag3 supports Foxp3+ regulatory T cell function by restraining Myc-dependent metabolic programming, Immunity (2024). DOI: 10.1016/j.immuni.2024.08.008

Journal information: Immunity 

Provided by Northwestern University