Engineered IL-39 cytokine unlocks new pathways for immunotherapy

In a new preclinical study, scientists present a molecular engineering approach to modify and repurpose a cytokine named IL-39, which plays a central role in inflammation and immunity. In addition to underscoring the potential of rational cytokine engineering, their findings also provide clues about whether IL-39 is found in the human body – a longstanding debate in immunology.

Interleukins fine-tune the functions of the body's immune cells, and researchers have identified more than 40 different types in humans to date. However, there are other interleukins that are less well-characterized, including IL-39. This signaling molecule is known to exist in mice, and studies have hinted it also shapes immune defenses in humans and might be involved in inflammatory disorders. However, the cytokine's existence in humans is still debated.

In search of answers, Chantal Bergmann and colleagues closely studied the purported formation of IL-39 in human kidney cells from its two molecular subunits: IL-23α and EBI3. Using computer models and experimental techniques, they found that the two subunits didn't readily form IL-39 in the human cells. They identified structural features in each subunit that prevented them from forming stable bonds, suggesting that IL-39 may not appear naturally in humans.

However, the team leveraged their insights and engineered each subunit to form stable bonds, resulting in a complete form of IL-39 that could be secreted by cells. This rationally designed IL-39 bound to the receptors IL-23R and gp130 and stimulated inflammatory pathways in cultured human immune cells, suggesting that similar approaches could be deployed to activate immune pathways. "Together, our findings define limitations in the biogenesis of human IL-39 and show that these can be overcome by molecular engineering," the authors conclude.