IL-12 family members are particularly relevant but also demanding clients of the cellular protein biogenesis and quality control machinery. In a molecular jigsaw, heterodimers have to be assembled from shared subunits to elicit the desired downstream immune responses, and structure formation as well as assembly have to be tightly controlled and regulated. Our lab has provided fundamental insights into how cells make IL-12 family cytokines, including IL-12 (Reitberger et al, 2017 J Biol Chem [read]), IL-23 (Meier et al, 2019 Nat Commun [read]) and IL-27 (Müller et al, 2019 PNAS [read]). We could show that assembly-dependent structure formation governs human IL-12 family cytokine biogenesis and that a large number of ER chaperones control this process (Hildenbrand et al, 2022 TIBS [read]).

Building on these discoveries, we are now embarking on the study of new IL-12 family members and other cytokines beyond this family. Many of these remain ill-characterized in structural and functional terms. We thus use biochemical and biophysical approaches to study cytokines in vitro, but also combine these with functional immunological assays to define their receptors and biological roles in our immune system. As an example, our recent work has led to a major change in our understanding of IL-35, revealing that it is not strictly secreted as a heterodimer. Our findings suggest that IL-35 subunits may function independently as cytokines, extending our understanding of human immune regulation but also opening up new possibilities for engineering cytokines and future therapies (Hildenbrand and Bohnacker et al, 2023 Science Advances [read]).