title: Antibodies to Interleukin-2 Elicit Selective T Cell Subset Potentiation through Distinct Conformational Mechanisms.
abstract: Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates immune cell homeostasis and has been used to treat a range of disorders including cancer and autoimmune disease. IL-2 signals via interleukin-2 receptor-β (IL-2Rβ):IL-2Rγ heterodimers on cells expressing high (regulatory T cells, Treg) or low (effector cells) amounts of IL-2Rα (CD25). When complexed with IL-2, certain anti-cytokine antibodies preferentially stimulate expansion of Treg (JES6-1) or effector (S4B6) cells, offering a strategy for targeted disease therapy. We found that JES6-1 sterically blocked the IL-2:IL-2Rβ and IL-2:IL-2Rγ interactions, but also allosterically lowered the IL-2:IL-2Rα affinity through a "triggered exchange" mechanism favoring IL-2Rα(hi) Treg cells, creating a positive feedback loop for IL-2Rα(hi) cell activation. Conversely, S4B6 sterically blocked the IL-2:IL-2Rα interaction, while also conformationally stabilizing the IL-2:IL-2Rβ interaction, thus stimulating all IL-2-responsive immune cells, particularly IL-2Rβ(hi) effector cells. These insights provide a molecular blueprint for engineering selectively potentiating therapeutic antibodies.
authors.affiliation: Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jamie B
authors.initials: JB
authors.lastname: Spangler
authors.affiliation: Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, 14220 Prague 4-Krc, Czech Republic.
authors.forename: Jakub
authors.initials: J
authors.lastname: Tomala
authors.affiliation: Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Luca
authors.affiliation: Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Jude
authors.affiliation: Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Shen
authors.initials: S
authors.lastname: Dong
authors.affiliation: Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Ring
authors.affiliation: Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, 14220 Prague 4-Krc, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Votavova
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109, USA.
authors.forename: Marion
authors.initials: M
authors.lastname: Pepper
authors.affiliation: Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, 14220 Prague 4-Krc, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Kovar
authors.affiliation: Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: kcgarcia@stanford.edu.
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000276:immunology; D001667:Binding, Competitive / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D000906:Antibodies; D007376:Interleukin-2