University of Dundee

Cytokine Signalling – Timing is everything

14 Jan 2020

Researchers in the Moraga group report the engineering of new tools to manipulate the immune response with the potential to treat human disorders. The research was done in collaboration with the Kazemian group (Purdue University, USA) and Mitra group (Centre de Recherche Jean-Pierre Aubert, France). The research was published in the journal eLife.

Cytokines comprise a large family of secreted ligands that control virtually every aspect of the immune response. Deregulation of cytokine activities results in disease, making this group highly relevant for human health and a very attractive drug target. However, different cytokines can have overlapping functions, which impedes the quest for cytokine-modulating drugs for therapeutic use.

Previous studies described that adjustments of the cytokine-receptor binding properties could impact cytokine signalling to better control cytokine bioactivities. However, exactly how cytokine-receptor binding parameters influence signalling and biological responses remains poorly defined. To address this question, the Moraga group has used IL-6, a cytokine that is critical for the regulation of the immune response, as a model system to engineer a series of IL-6 variants that bind their receptor with different dwell-times.

The engineered IL-6 variants exhibited a range of signalling amplitudes and induced biased signalling, which resulted from defective translocation of short-lived IL-6-receptor complexes to the endosomal compartments. This in turn led to a graded gene expression response and different capabilities to induce the formation of different types of immune cells ex vivo. These results highlight that cytokine-receptor binding dwell-time fine-tunes signalling identity by cytokines and demonstrate that manipulation of cytokine signalling thresholds is a useful strategy to decouple cytokine functional pleiotropy and reduce toxicity in cytokine-based therapies.

The research was conducted within the School of Life Sciences at Dundee, funded by a European Research Council starting grant and a Sir Henry Dale Royal Society/Wellcome Trust Fellowship.