Run the first half of a marathon as fast as you can and you’ll likely never finish the race. Run an engine at top speed for too long and you’ll burn it out.
The same principle seems to apply to our T cells, which power the immune system’s battle with chronic infections like HIV and hepatitis B, as well as cancer. Too often, they succumb to “T cell exhaustion” and lose their capacity to attack infected or malignant cells. But could T cells learn to pace themselves and run the full marathon?
That’s the thinking behind a research study published last week by The Journal of Experimental Medicine. “Our research provides a clear explanation for why T cells lose their fighting ability,” says Florian Winau, MD, “and describes the countervailing process that protects their effectiveness.”
A respite for burned-out T cells
T cells go into action when receptors on their outer membrane detect antigens of diseased cells. They stay in action, working to destroy the “bad” cells, as long as the receptors keep signaling the presence of antigens. Winau and colleagues in the Program in Cellular and Molecular Medicine at Boston Children’s Hospital found that a naturally occurring protein effectively suppresses receptor signaling, giving T cells a restorative break in the action.
“This protein — technically called Transmembrane Protein 16F or TMEM16F — allows a normal, full-bore response by the T cell when it first encounters the antigens,” explains Yu Hu, PhD, a postdoctoral researcher in Winau’s lab. “But thereafter, it will help to encase some of the antigen receptors in lipid vesicles that degrade them. As a result, the T cell perceives less of a threat and scales down its response to the infectious element.” That lower-level response enables the T cell to sustain its attack on the enemy cells.
The researchers demonstrated TMEM16F’s restorative role by showing what happens when T cells lack the protein. In mice that were TMEM16F-deficient, T cells initially responded to infection in a hyperactive manner — and then continued at a too-strong-to-maintain level. The T cells eventually burned out, becoming completely dysfunctional. The result: infected cells remained, in abundance. “In comparison, mice that had normal levels of TMEM16F successfully cleared the virus,” says Winau.
The basic function of TMEM16F was discovered six years ago by Japanese researcher Shigekazu Nagata and his colleagues, who determined that it helped to shuffle lipids between the layers of the cell membrane. Winau’s lab discovered its role in T lymphocytes: encasing antigen receptors and ensuring the T cells’ long-lasting infection-fighting ability.
Boosting long-term immune response
Plus, the Boston Children’s researchers found that TMEM16F has another important benefit for the immune system. A small subset of the T cells — called T-bethi cells — has the capacity to replenish the pool of antiviral T cells. TMEM16F helps these T-bethi cells thrive, ensuring a sufficient number of functional T cells to battle the infection.
“TMEM16F is essential for the immune system to produce an army of infection-fighters that is both numerous enough and potent enough to outlast and overcome invading infectious agents,” Hu suggests.
The T-bethi finding is also interesting because cancer research has shown that existing drugs can boost the potency of T-bethi populations, strengthening the immune response.
“We already knew that drugs that reinvigorate T-bethi cells by blocking the ‘programmed death protein’ PD-1 can be effective in treating a wide range of cancers,” says Winau.
Like the protein itself, the TMEM16F findings are energizing Winau and his colleagues to seek answers to the next questions: Can targeted activation of TMEM16F enlarge the T-bethi pool? And could this approach be used together with immune checkpoint inhibitors to improve therapy for chronic infection and cancer?
“We already have proof-of-concept for using enhanced immune system function to fight chronic infection and cancer,” Winau says. “And TMEM16F may prove to be another route for doing that.”