title: Insights into cytokine-receptor interactions from cytokine engineering.
abstract: Cytokines exert a vast array of immunoregulatory actions critical to human biology and disease. However, the desired immunotherapeutic effects of native cytokines are often mitigated by toxicity or lack of efficacy, either of which results from cytokine receptor pleiotropy and/or undesired activation of off-target cells. As our understanding of the structural principles of cytokine-receptor interactions has advanced, mechanism-based manipulation of cytokine signaling through protein engineering has become an increasingly feasible and powerful approach. Modified cytokines, both agonists and antagonists, have been engineered with narrowed target cell specificities, and they have also yielded important mechanistic insights into cytokine biology and signaling. Here we review the theory and practice of cytokine engineering and rationalize the mechanisms of several engineered cytokines in the context of structure. We discuss specific examples of how structure-based cytokine engineering has opened new opportunities for cytokines as drugs, with a focus on the immunotherapeutic cytokines interferon, interleukin-2, and interleukin-4.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305; email: kcgarcia@stanford.edu , jamie.spangler@stanford.edu , imoraga@stanford.edu , juan.mendoza@stanford.edu.
authors.forename: Jamie B
authors.initials: JB
authors.lastname: Spangler
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moraga
authors.forename: Juan L
authors.initials: JL
authors.lastname: Mendoza
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
mesh_terms: D000818:Animals; D016207:Cytokines / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D005818:Genetic Engineering; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D018121:Receptors, Cytokine / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D018121:Receptors, Cytokine
keywords: immune signaling; immunotherapeutics; interferon; interleukin; ligand-receptor interaction; protein design