The pathways that exist to regulate biological function are extensive, and often they can be manipulated to cause wanted as well as unwanted actions. A team of scientists from the Immunology group at Vanderbilt reports their findings in the scientific journal Cell describing the amino acid glutamine and its effects on T cell signaling.
Amino acids are the organic compounds containing both a carboxyl (-COOH) and amino (-NH2) group. There are 20 naturally occurring amino acids that when put into particular sequences, make up the proteins that carry out the functions organisms at the molecular level. The amino acid glutamine is described to launch a metabolic pathway that promotes the function of some immune system T cells and suppresses others.
Jeffery Rathmell, Ph.D., Professor of Immunobiology at Vanderbilt along with a team of researchers show that a drug capable of inhibiting glutamine metabolism could have the potential also to be used as mitigation to inflammatory and autoimmune diseases. Furthermore, their published work suggests the drug could be used to enhance cancer immunotherapies.
The team has focused their work on the mechanisms at play when a cell integrates its nutrients and metabolism with its function. The Vanderbilt team describes glucose, a source of energy for the cell, activates and drives T cell function known to increase inflammation and pathogen removal.
Glutamine can also act as fuel for the cell. For this reason, the team was interested in taking a deeper dive into its role in the context of cancer metabolism. The industry is currently manufacturing drugs that will inhibit glutamine to reduce the growth of the cancer cells.
Here, the team hopes that if they inhibit glutamine metabolism, there is a good chance that T cell activation and function driving inflammation would be blocked. To carry this idea to fruition, the team makes use of the enzyme known as glutaminase. Furthermore, the scientists utilize mouse models that have the genes encoding glutaminase deleted.
"This compound (that inhibits glutaminase) works in some tumors and doesn't work in others. What Marc found is that it's the same for T cells: some T cells need this pathway, and some don't," Rathmell reports. "If we block the pathway, the autoimmune T cells don't do so well, but the anticancer T cells do better."
A graduate student remarked his interest in the metabolic pathway having various impacts on the function of T cell subsets. Professor Rathmell shares that their work seems to be in line with the results of the work done on glutamine metabolism in cancer cells.
The elimination of glutaminase activity protected against inflammatory responses in murine models of asthma, inflammatory bowel, and graft vs. host disease. Additionally, the team shares that not only is the inhibitor effective, it is also remarkably safe, “ The glutaminase inhibitor has a remarkable safety profile, and we think it could be repurposed in potentially quite a variety of inflammatory and autoimmune diseases."
"By changing this metabolic enzyme, we're affecting a downstream metabolite that directly changes chromatin and gene accessibility and gene expression," Rathmell said. "As a concept, this idea that metabolic pathways are signaling pathways is relatively new."