title: Multifarious determinants of cytokine receptor signaling specificity.
abstract: Cytokines play crucial roles in regulating immune homeostasis. Two important characteristics of most cytokines are pleiotropy, defined as the ability of one cytokine to exhibit diverse functionalities, and redundancy, defined as the ability of multiple cytokines to exert overlapping activities. Identifying the determinants for unique cellular responses to cytokines in the face of shared receptor usage, pleiotropy, and redundancy will be essential in order to harness the potential of cytokines as therapeutics. Here, we discuss the biophysical (ligand-receptor geometry and affinity) and cellular (receptor trafficking and intracellular abundance of signaling molecules) parameters that contribute to the specificity of cytokine bioactivities. Whereas the role of extracellular ternary complex geometry in cytokine-induced signaling is still not completely elucidated, cytokine-receptor affinity is known to impact signaling through modulation of the stability and kinetics of ternary complex formation. Receptor trafficking also plays an important and likely underappreciated role in the diversification of cytokine bioactivities but it has been challenging to experimentally probe trafficking effects. We also review recent efforts to quantify levels of intracellular signaling components, as second messenger abundance can affect cytokine-induced bioactivities both quantitatively and qualitatively. We conclude by discussing the application of protein engineering to develop therapeutically relevant cytokines with reduced pleiotropy and redirected biological functionalities.
authors.affiliation: Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, California, USA; Program in Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moraga
authors.affiliation: Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, California, USA; Program in Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Spangler
authors.affiliation: Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, California, USA; Program in Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Juan L
authors.initials: JL
authors.lastname: Mendoza
authors.affiliation: Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, California, USA; Program in Immunology, Stanford University School of Medicine, Stanford, California, USA. Electronic address: kcgarcia@stanford.edu.
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
mesh_terms: D000818:Animals; D000939:Epitopes / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D008024:Ligands; D061251:Primary Cell Culture; D011485:Protein Binding / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D018121:Receptors, Cytokine / Q000378:metabolism / Q000502:physiology*; D015290:Second Messenger Systems / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D000939:Epitopes; D008024:Ligands; D018121:Receptors, Cytokine
keywords: Cytokine engineering; Cytokine signaling; Cytokine structure; Functional specificity; Interleukin; Ligand–receptor affinity; Receptor trafficking