In a study published today in Cell, Vanderbilt researchers have shown that glutamine launches a metabolic signaling pathway that promotes the function of some immune system T cells and suppresses others. They show that a drug that inhibits glutamine metabolism—currently in clinical trials as an anticancer agent—might also be useful as a treatment for inflammatory and autoimmune diseases.
Senior author Jeffrey Rathmell and colleagues have focused on understanding how cells integrate nutrients and metabolism with function. They previously demonstrated the importance of the cellular fuel glucose for activation and function of T cells.
The investigators expected that inhibiting glutamine metabolism, like blocking glucose metabolism, would prevent T cell activation and function. They tested their hypothesis using two approaches: (1) administering a drug that inhibits the enzyme glutaminase, which is the first step in glutamine metabolism, and (2) studying mice with a targeted genetic deletion of the glutaminase gene. To their surprise, they found that certain T cells—those that mediate antiviral and anticancer responses—performed better in the absence of glutaminase activity, while T cells involved in inflammatory and autoimmune diseases performed worse.
The researchers also demonstrated that in mouse models of allergic asthma, inflammatory bowel disease, and chronic graft-versus-host disease that eliminating glutaminase activity protected against inflammation and disease.
"The glutaminase inhibitor has a remarkable safety profile,” says senior author Jeffrey Rathmell, “and we think it could be repurposed in potentially quite a variety of inflammatory and autoimmune diseases."
To examine the impact of inhibiting glutaminase on T cells that mediate anticancer responses, the investigators used the drug in a mouse model of CAR (chimeric antigen receptor) T-cell therapy. CAR T cells are cancer-killing T cells that have been genetically engineered to recognize specific cancer cells.
"One of the problems with CAR T-cell therapy is survival of the engineered cells," says first author Marc Johnson. "We think that a short treatment with a glutaminase inhibitor might improve the persistence of CAR T cells."
The researchers also looked into the mechanistic changes that resulted from glutaminase inhibition. They demonstrated that the glutamine metabolic pathway—usually thought of only in terms of energy generation—is tightly integrated with cell signaling and gene expression.