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Links between immune cells and metabolism explored

Nov. 10, 2016, 8:29 AM

Jeffrey Rathmell, Ph.D., said Vanderbilt has exceptional strengths in the emerging field of immunometabolism. (photo by Susan Urmy)
Jeffrey Rathmell, Ph.D., said Vanderbilt has exceptional strengths in the emerging field of immunometabolism. (photo by Susan Urmy)

At the intersection of immunology and metabolism is a burgeoning new field: immunometabolism. It’s an area where Vanderbilt has exceptional strengths, said Jeffrey Rathmell, Ph.D., Cornelius Vanderbilt Professor of Immunobiology.

“It’s an unsung area of expertise here,” said Rathmell, who is also professor of Pathology, Microbiology and Immunology and professor of Cancer Biology. “There are many labs working independently in different areas of this topic across the University and Medical Center, but all under the umbrella of immunometabolism.”

Immunometabolism is one of the research focus areas of the recently established Vanderbilt Center for Immunobiology, which Rathmell directs.

The field has its roots in the finding that obesity leads to an inflammatory response that drives insulin resistance and type 2 diabetes. Broadly defined, research in immunometabolism explores the links between metabolism and inflammation and also how the metabolism of immune system cells regulates their function.

In one area of their research, Rathmell and his colleagues have focused on how signals that regulate metabolism in T cells impact cell function.

The group previously demonstrated that the metabolism of effector T cells — cells that drive inflammation and eliminate pathogens — depends on glucose and is geared towards biosynthesis and growth. Conversely, regulatory T cells (T-regs), which help control inflammation to resolve infections, have a metabolism that uses lipids and is not growth-directed.

“As a result of their metabolism, our work predicted that T-regs won’t grow very well,” Rathmell said. “But we know they can actually proliferate really well, so how are they doing that?”

In a recent paper in Nature Immunology, Rathmell and his colleagues reported that multiple signals regulate the metabolism of T-regs. Inflammatory signals increase glucose-dependent metabolism, which promotes the proliferation of T-regs but disables their immune-suppressing capabilities. The transcription factor Foxp3, a master regulator of T-regs, promotes lipid metabolism and suppressive function.

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

The findings make sense in the context of a normal infection, he explained.

The presence of a pathogen launches an immune response, and effector T cells go to the site to control the infection. Regulatory T cells also go to the site, and in response to the inflammatory signals, they grow and proliferate, but they don’t suppress the inflammation. As the effector T cells work to control the infection, the inflammatory signals decline. The T-regs are in place, and they can switch to their lipid-based suppressive metabolism to promote resolution of the infection and 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.”

The team has demonstrated the importance of this metabolic switch using mice with T-regs that have been genetically modified to always have a high glucose metabolism. The T-regs in these mice don’t suppress the immune response, and the mice develop a lupus-like disease.

The findings may explain the observation that patients with lupus, rheumatoid arthritis and other chronic inflammatory diseases have large populations of T-regs that 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?”

Rathmell plans to build connections between investigators at Vanderbilt who are working in the area of immunometabolism.

“The whole field is very well represented here, and we look forward to working together to move it forward,” he said.

To see a list of Vanderbilt investigators studying immunometabolism and metabolic disease, visit the Center for Immunobiology website.

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