Metabolic Switch May Explain Failure in Immune Cells to Control Inflammation in Lupus Patients

Researchers discovered a new mechanism linking specific classes of immune cells and metabolism, a finding that may explain why patients with lupus are incapable of controlling the inflammatory responses that ultimately lead to disease.

The study, “Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression,” was published in the journal Nature Immunology.

Our immune system is composed by a complex repertoire of immune cells. Among these, we have effector T-cells, which are important to drive inflammation and eliminate pathogens. Conversely, regulatory T-cells (Tregs) are another class of immune cells that help control inflammation to resolve infections.

Not only do effector T-cells and Tregs have different roles, but to function they also depend on different metabolic pathways – effector T-cells depend on glucose and their metabolism is directed for biosynthesis and growth, while Tregs use lipids and their metabolism is not growth-directed.

“As a result of their metabolism, our work predicted that T-regs won’t grow very well,” Jeffrey Rathmell, PhD, Cornelius Vanderbilt Professor of Immunobiology, Vanderbilt University Medical Center, said in a press release. “But we know they can actually proliferate really well, so how are they doing that?”

To answer this question, researchers conducted additional investigated into the metabolism of Tregs.

The team found that Tregs’ metabolism is regulated by several signals, and one of these signals is inflammation. While inflammatory signals induce a glucose-dependent metabolism, thereby promoting Tregs’ proliferation, there is an additional effect: This metabolic programming disables Tregs’ functions to suppress the immune system.

A master regulator of Tregs called Foxp3 was shown to promote lipid metabolism and Tregs’ suppressive function.

Hence, “The inflammatory signals and Foxp3 are opposing each other, and the result depends on whoever wins,” Rathmell explained.

These new findings shed light on what occurs in the context of an infection. After an immune response is activated by the presence of a certain pathogen, effector T-cells go to the site to control the infection. Tregs are also recruited to the infection site, and while inflammatory signals are active, Tregs grow and proliferate, but they don’t suppress the inflammation.

As the effector T-cells are actively fighting the infection, inflammation starts to decrease. Tregs, located at the site, can now switch to their lipid-based suppressive metabolism and control the immune response to resolve the infection and promote healing.

“It’s all balanced. As long as there’s an inflammatory signal there, the T-regs are going to be balanced as to how strongly they can work to turn the response down,” Rathmell said. “The metabolic switch helps tip the balance between the two.”

By performing in vivo experiments, researchers showed the importance of this metabolic switch. Using genetically modified mice to always have a high glucose metabolism, they showed that Tregs in these mice do not suppress the immune response. This means that the immune system continues to be activated and mice develop a lupus-like disease.

This may explain why patients with lupus and other chronic inflammatory diseases, although carrying large populations of Tregs, are not suppressing the disease, Rathmell said. “That’s a question we’re exploring now — do chronic inflammatory settings mediate metabolic changes to the T-regs that impact their function?”