Rogue immune cells that ‘steal’ proteins may worsen multiple sclerosis

30 MAR 2022 2:45 PM

BY MITCH LESLIE

When a T cell and a B cell embrace, the T cell may acquire a key protein. DENNIS KUNKEL MICROSCOPY/SCIENCE SOURCE

Multiple sclerosis (MS)—an autoimmune disease in which immune cells strip the protective myelin insulation from nerves—has long puzzled researchers. One key mystery is which of the body’s immune cells go rogue—and why. Now, a new study suggests that as some T cells set out on their path of destruction, they swipe a critical protein from another type of immune cell, called B cells. Targeting these larcenous T cells could open the door to new MS therapies with fewer side effects.

“This study is very important,” says neuroimmunologist Joseph Sabatino of the University of California, San Francisco. It is the first to show some T cells purloin a protein called CD20 from the surface of B cells, he adds. That behavior may signal that the T cells have become more harmful.

In earlier research, scientists had noticed a rare subset of T cells that carry CD20. Although these cells occur in healthy people, they are more abundant in patients with MS, and lab studies suggested they could be particularly destructive. Yet how these T cells end up with CD20—which is a defining feature of B cells—and how they promote nerve damage in MS remained unclear.

The plot thickened when neuroimmunologist Martin Weber of the University Medical Center Göttingen and colleagues began to probe the cells. They discovered that mouse T cells sporting CD20 did not make the protein themselves. So where did it come from? One possible source was other immune cells, which often cozy up to T cells in the spleen and lymph nodes. During these trysts, T cells might nab CD20 from their partners.

Weber and colleagues set out to test that explanation using cells from healthy mice. First, they grew the animals’ B cells together with T cells that had no CD20 in a lab dish. Sure enough, after 1 to 2 days, the T cells acquired the protein, the team reports today in Science Translational Medicine. But when there was a barrier between the two types of cells, the T cells remained CD20-free. That suggests the T cells need “direct and close molecular contact” to pick up the protein, Weber says. The researchers obtained similar results when they grew human T and B cells together.

Still, what happens in a culture dish doesn’t always happen in the body. So Weber and his team investigated whether T cells snatch CD20 from B cells in living mice. They used genetically modified rodents that lack B cells and harbor almost no CD20-positive T cells. Once the researchers infused fresh B cells into the mice, numerous CD20-carrying T cells appeared in the animals’ blood, spleen, and lymph nodes.

The study also bolsters the case that these rogue T cells are helping wreak destruction in MS. The researchers determined that T cells with CD20 produced more inflammation-stimulating molecules than did cells without the protein, for instance. They also outfitted their membranes with more of the sticky proteins that can help them slither into nerves, where they could cause damage.

CD20 itself doesn’t make the T cells harmful, Weber says. But it may indicate the T cells have been switched on by B cells and are ready to begin to attack myelin. T cells are usually activated by a different type of immune cell, so researchers still need to determine what circumstances bring the B and T cells together and where these liaisons occur, says immunologist Steven Kerfoot of Western University in Canada.

The work offers clues as to the causes of MS, but it may also hold implications for treatment. MS patients often receive therapies that target immune cells carrying CD20, which scientists traditionally assumed were B cells. But recent studies have shown the drugs also cull the CD20-carrying T cells, whose demise could explain why patients improve.

Whether the drugs work by killing the CD20-positive T cells remains unclear, says immunologist Joan Goverman of the University of Washington, Seattle. But if researchers confirm that mechanism, it might be possible to design new, more specific treatments that could eliminate the aggressive T cells—without causing the often-severe side effects that result from a loss of B cells. That could, in turn, improve the lives of people with MS.