Floß Group

Cytokines regulate the immune system as humoral mediators. Cellular communication is supported by four distinct types of cytokine receptors, categorized by their main signaling pathway: (1) receptors that activate NFκB and MAP kinases (mainly p38 and JNK); (2) receptors that activate the JAK-STAT pathway; (3) TGFβ receptors; and (4) the growth factor receptor family, which typically triggers the ERK pathway. Most cytokines, including IL-12 type cytokines, signal through class I/II cytokine receptors, which are associated intracellularly with Janus kinases (JAKs). The interleukin 12 family plays a key role in regulating innate and adaptive immune responses and includes five members (IL-12, IL-23, IL-27, IL-35, and IL-39). These consist of a four-helix-bundle α-subunit (such as IL-23p19, IL-27p28, or IL-12p35) and a β-subunit (IL-12p40 or EBI3), which is structurally related to soluble cytokine receptors. This family uses five class I cytokine receptors. IL-12 type cytokines specifically use IL-12Rβ1, IL-12Rβ2, and IL-23R, while gp130 and WSX-1 are shared with the IL-6 cytokine family. As a result, IL-6 and IL-12 type cytokines are often grouped as the IL-6/IL-12 cytokine family. Despite sharing many subunits and receptors, IL-12 family cytokines produce a broad and diverse range of immune responses. Our group has contributed to understanding cytokine-receptor interactions by identifying binding sites for IL-23 and IL-12 with their specific receptors. Gaining a deeper understanding of the structural aspects of receptor complex formation and signaling pathways of IL-12-type cytokines is essential for developing innovative therapies aimed at preventing or inhibiting cytokine-receptor interactions.

Mutations that cause ligand-independent, constitutive activation of cytokine receptors are often found in diseases. Naturally occurring gain-of-function mutants have been identified in patients for various cytokine receptors. Although this constant activation of cytokine receptors is closely linked to malignant disorders, ligand-independent receptor activation also benefits synthetic biology by modulating cell signaling. These gain-of-function receptors are based on mutations within the extracellular, transmembrane, or intracellular domains. Using natural principles in developing synthetic constitutive active cytokine receptors has become an important area of research. We have already shown that introducing the PPCL transmembrane domain of a constitutively active IL-7Rα is enough to trigger ligand-independent activation of both natural and synthetic class I/II cytokine receptors. Natural principles can be applied to create synthetic constitutive active cytokine receptors, enhancing adoptive cellular therapies with genetically engineered T cells or NK cells.