Inflammation can help the human body fight off infections. If left unchecked, it can also lead to a variety of inflammatory disorders, such as gout and lupus. Now scientists find that in mice, a kind of immune cell that normally promotes inflammation can naturally get genetically reprogrammed into another kind of immune cell that reduces inflammation.
“If you can control this response, then hopefully you can shut down disorders like multiple sclerosis, psoriasis and rheumatoid arthritis,” says study co-senior author Richard Flavell, chair of immunobiology at Yale University at New Haven, Conn.
Inflammation helps protect the body against infection and injury by destroying foreign and damaged cells. But if it gets out of control, inflammation can damage healthy tissue. One kind of immune cell known as a T helper 17 (TH17) cell is known to promote inflammation via small proteins called cytokines; this can lead to severe inflammatory diseases such as multiple sclerosis and rheumatoid arthritis.
Prior research suggested that TH17 cells could sometimes cease secreting their signature cytokine, IL-17A, and even start expressing cytokines typical of other kinds of cells. However, it was uncertain whether these changes merely reflected a few changes in what molecules TH17 cells generated, or whether they had actually converted into another kind of T helper cell, a process known as transdifferentiation.
Hoping to solve this mystery, Flavell and his colleagues tracked the fate of TH17 cells during immune responses in mice. The mice were genetically modified so their TH17 cells generated yellow fluorescent protein even if they no longer secreted IL-17A. The scientists found that about half of all TH17 cells that had generated IL-17A eventually stopped generating IL-17A. They dubbed these ex-TH17 cells.
Based on the molecules seen on the surfaces of the ex-TH17 cells, as well as on RNA molecules linked with gene activity within the cells, Flavell and his colleagues found that during immune responses, about 4.3 percent of these ex-TH17 cells changed to resemble a kind of immune cell known as a regulatory T cell or TR cell, which helps reduce inflammation. They detailed their findings in the July 9 Nature.
“The fact that a TH17 cell could turn on its head and become a regulatory T cell is a bit of a surprise,” Flavell says. The scientists also found that during infections with worms or bacteria, TH17 cells that became TR cells could secrete anti-inflammatory proteins that could limit destructive immune responses.
“Although we still don’t know if this occurs in humans, this study paves the way to new therapeutical strategies in which the induction of T cell transdifferentiation can be exploited to shift from an inflammatory to an immunosuppressed environment,” says immunologist Eduardo Villablanca at the Karolinska Institute in Stockholm, who did not take part in this research.
Previous research suggested that TH17 cells could also convert into another kind of cell—one resembling a different kind of T helper cell known as a TH1 cell—that is also known to provoke inflammatory diseases. Flavell and his colleagues now plan to explore all the different types of cells that TH17 cells can become.