A metabolic enzyme that has been studied in cancer biology and is important for T cell function may offer a new target for anti-inflammatory therapeutics, researchers have discovered. They report that inhibiting or genetically deleting the enzyme, called MTHFD2, reduced disease severity in multiple inflammatory disease models.
Jeffrey Rathmell, PhD, Cornelius Vanderbilt Professor of Immunobiology, and his team are interested in how metabolic pathways — the chemical reactions that sustain life — influence immune cell function. In the current studies, they focused on «one-carbon» metabolism, a series of reactions that generates chemical building blocks for the biosynthesis of DNA and other molecules.
«One-carbon metabolism has been a target for drug development for years and years, but it really hasn’t been explored in an unbiased way,» said Rathmell, who is also director of the Vanderbilt Center for Immunobiology. The immunosuppressant drug methotrexate, for example, inhibits an enzyme in the one-carbon metabolism pathway, but it may not be the «right target or the right drug» for optimal therapeutic activity, he said.
To systematically study the pathway in T cells — white blood cells that respond to specific antigens (such as surface proteins on viruses) — Ayaka Sugiura, an MD-PhD student in Rathmell’s group, developed a screening strategy using the genome editing technology CRISPR. She designed CRISPR «guides» to selectively inactivate each gene in the one-carbon metabolism pathway and introduced this «library» into isolated T cells, carefully controlling the experimental conditions so that each cell had only one (or no) inactivated gene.
By studying the modified cells in an animal model of asthma, Sugiura was able to identify genes important to T cell function during the disease process. She then examined the expression of each identified gene during T cell development and in patients with a variety of inflammatory diseases.
MTHFD2 stood out. It was highly expressed in disease states and during embryonic development, but it was expressed at low levels, or not at all, in adult tissues, Sugiura said.
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Materials provided by Vanderbilt University Medical Center. Original written by Leigh MacMillan. Note: Content may be edited for style and length.