Engineered subunits yield human IL-39 cytokine that is secreted and activates immune cells in vitro
In human cells, IL-23α and EBI3 did not readily form IL-39. Modeling-guided disulfide engineering produced a secreted, active heterodimer in a preclinical study.
Chantal Bergmann and colleagues reported in Science Signaling on 3 November 2026 that interleukin-39 (IL-39) does not readily form from its two subunits, IL-23α and EBI3, in human cells. The team then engineered the subunits so that they assemble into a stable heterodimer doi.org
Science Signalingdoi.orgOpen source ↗. The study is preclinical and was carried out in cultured cells.
Why the existence of IL-39 is debated
Interleukins are signaling proteins that control immune responses, and more than 40 types have been identified in humans. IL-39, a heterodimer of IL-23α and EBI3, has been described as a proinflammatory cytokine in mice. Its place in the human interleukin repertoire has remained controversial doi.org
Science Signalingdoi.orgOpen source ↗. Earlier studies hinted that it may also shape immune defenses in humans and may be involved in inflammatory disorders.
The authors examined the formation of IL-39 from the two subunits in human kidney cells. Computer modeling combined with experiments showed that the subunits did not readily form the heterodimer. The team identified structural features that destabilize the human IL-23α:EBI3 heterodimer doi.org
Science Signalingdoi.orgOpen source ↗. According to the release accompanying the paper, this suggests that IL-39 may not appear naturally in humans.
Engineered heterodimer and its activity
Using these structural insights, the authors rationally engineered human IL-23α and EBI3 to form disulfide-linked heterodimers. Cells secreted the resulting engineered cytokine doi.org
Science Signalingdoi.orgOpen source ↗.
On primary human immune cells, the engineered protein engaged the receptor subunits IL-23R and gp130. It stimulated phosphorylation of the transcriptional regulators STAT1 and STAT3, and the cells secreted proinflammatory cytokines in response doi.org
Science Signalingdoi.orgOpen source ↗.
The authors conclude that the biogenesis of human IL-39 has limitations and that molecular engineering can overcome them. They say the work highlights the potential of rational cytokine engineering for generating active immune signaling proteins. They also say it lays the foundation for further defining possible roles of IL-39 in human immunity doi.org
Science Signalingdoi.orgOpen source ↗. The engineered molecule was tested in cell culture only.
