Abstract: Our group has found that the fusion of GM-CSF to members of γ-c interleukins result in the generation of novel proteins with unique signaling properties and unheralded biological effects. These fusion proteins, termed GIFT fusokines (GM-CSF Interleukin Fusion Transgenes) are the result of combining GM-CSF and a γ-common chain interleukin into a single, bi-functional polypeptide. In our experience, GIFT fusokines often confer immune cells with a gain-of-function that cannot be explained by the mere sum of their constituent moieties. They act as bi-specific ligands, coupling activated GM-CSF and interleukin receptors together to drive unique downstream signaling events. The synergy that arises from these fusions have shown great promise in their ability to modulate the immune response and overcome maladaptive biological processes that underlie diseases such as autoimmune conditions. In this seminar, I will discuss the ways in which the GIFT15 fusokine converts normal B-cells to IL-10+ B-regulatory cells which can reverse acute neuroinflammatory disorders with a special emphasis on how these novel molecules may be translated into effective therapies in the clinical setting.