Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines

Cytokines dimerize their receptors, with binding of the “second chain” triggering signaling. In the interleukin (IL)-4/13 system, different cell types express varying levels of alternative second receptor chains (γc or IL-13Rα1), forming functionally distinct Type-I or Type-II complexes. We manipulated the affinity and specificity of second chain recruitment by human IL-4. A Type-I receptor-selective IL-4 ‘superkine’ with 3700-fold higher affinity for γc was 3-10 fold more potent than wild-type IL-4. Conversely, a variant with high affinity for IL-13Rα1 more potently activated cells expressing the Type-II receptor, and induced differentiation of dendritic cells from monocytes, implicating the Type-II receptor in this process. Superkines exhibited signaling advantages on cells with lower second chain levels. Comparative transcriptional analysis reveals that the superkines induce largely redundant gene expression profiles. Variable second chain levels can be exploited to redirect cytokines towards distinct cell subsets and elicit novel actions, potentially improving the selectivity of cytokine therapy.