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.

Department of Immunology University of Washington Seattle WA 98109 USA

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

Laboratory of Tumor Immunology Institute of Microbiology of the Academy of Sciences of the Czech Republic 14220 Prague 4 Krc Czech Republic

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Immunity. 2015 May 19;42(5):779-81. doi: 10.1016/j.immuni.2015.05.002. PubMed

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