A team of researchers at Vanderbilt University Medical Center (VUMC) reports that blocking an iron uptake receptor reduces disease pathology and promotes the activity of anti-inflammatory regulatory T cells in a mouse model of systemic lupus erythematosus (SLE).

Their study, “Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus,” was published in Science Immunology.

Lupus, including SLE, occurs when the immune system attacks a person’s own healthy tissues, causing pain, inflammation, and tissue damage. About 1.5 million Americans and 5 million people worldwide have a form of lupus, according to the Lupus Foundation of America.

“It has been a real challenge to come up with new therapies for lupus,” explained Jeffrey Rathmell, PhD, professor of pathology, microbiology, and immunology and the Cornelius Vanderbilt chair in immunobiology. “The patient population and the disease are heterogeneous, which makes it difficult to design and conduct clinical trials.”

To explore T cell iron metabolism in lupus, postdoctoral fellow Kelsey Voss, PhD, and Rathmell drew on the expertise of other investigators at VUMC: Eric Skaar, PhD, Amy Major, PhD, and Michelle Ormseth, MD, along with their teams.

Voss used a CRISPR genome editing screen to evaluate iron-handling genes in T cells. She identified the transferrin receptor, which imports iron into cells, as critical for inflammatory T cells and inhibitory for anti-inflammatory regulatory T cells.

The researchers found that the transferrin receptor was more highly expressed in T cells from SLE-prone mice and T cells from patients with SLE, which caused the cells to accumulate too much iron.

“We see a lot of complications coming from that—the mitochondria don’t function properly, and other signaling pathways are altered,” Voss explained.

An antibody that blocks the transferrin receptor reduced intracellular iron levels, inhibited inflammatory T cell activity, and enhanced regulatory T cell activity. Treatment of SLE-prone mice with the antibody reduced kidney and liver pathology and increased production of the anti-inflammatory factor, IL-10.

“It was really surprising and exciting to find different effects of the transferrin receptor in different types of T cells,” Voss said. “If you’re trying to target an autoimmune disease by affecting T cell function, you want to inhibit inflammatory T cells but not harm regulatory T cells. That’s exactly what targeting the transferrin receptor did.”

The researchers are interested in developing transferrin receptor antibodies that bind specifically to T cells, to avoid any potential off-target effects (the transferrin receptor mediates iron uptake in many cell types). They are also interested in studying the details of their unexpected discovery that blocking the transferrin receptor enhances regulatory T cell activity.

Their findings demonstrate that targeting iron metabolism in immune system cells may offer a new approach for treating systemic lupus erythematosus, and may pave the way for new therapeutic strategies.

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