To reroute a cytokine’s signaling, Abhiraman et al. generated soluble adaptors comprising units that bind to two sites on a cytokine linked to units that bind to and compel dimerization/activation of a different cytokine’s receptor. Adaptors linking an scFv specific for dimeric TGFβ or an scFv to IL-10 and IL10R-domain to VHHs specific for IL-2Rβ or γc chains were shown to lack intrinsic signaling activity, but in the presence of immunosuppressive TGFβ or IL-10, respectively, agonized IL-2R mediated proinflammatory effector functions of human T cells in vitro. Structurally analogous adaptors converted proinflammatory IL-23 and IL-17 into immunosuppressive IL-10R agonists.
Contributed by Paula Hochman
ABSTRACT: Cytokines are signaling molecules that coordinate complex immune processes and are frequently dysregulated in disease. While cytokine blockade has become a common therapeutic modality, cytokine agonism has had limited utility due to the widespread expression of cytokine receptors with pleiotropic effects. To overcome this limitation, we devise an approach to engineer molecular switches, termed cytokine adaptors, that transform one cytokine signal into an alternative signal with a different functional output. Endogenous cytokines act to nucleate the adaptors, converting the cytokine-adaptor complex into a surrogate agonist for a different cytokine pathway. In this way, cytokine adaptors, which have no intrinsic agonist activity, can function as conditional, context-dependent agonists. We develop cytokine adaptors that convert IL-10 or TGF-_ into IL-2 receptor agonists to reverse T cell suppression. We also convert the pro-inflammatory cytokines IL-23 or IL-17 into immunosuppressive IL-10 receptor agonists. Thus, we show that cytokine adaptors can convert immunosuppressive cytokines into immunostimulatory cytokines, or vice versa. Unlike other methods of immune conversion that require cell engineering, cytokine adaptors are soluble molecules that leverage endogenous cues from the microenvironment to drive context-specific signaling.
Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. Program in Immunology, Stanford University
Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. Program in Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA. (2) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. Program in Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA. (3) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. Program in Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA. (4) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. (5) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. (6) Program in Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA. Department of Otolaryngology - Head & Neck Surgery, Stanford University School of Medicine, Stanford, CA, 94305, USA. (7) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. (8) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. (9) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. (10) Department of Surgery, University of Washington School of Medicine, Seattle, WA, 98112, USA. (11) Department of Surgery, University of Washington School of Medicine, Seattle, WA, 98112, USA. (12) Department of Otolaryngology - Head & Neck Surgery, Stanford University School of Medicine, Stanford, CA, 94305, USA. (13) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. kcgarcia@stanford.edu. Howard Hughes Medical Institute, Stanford University, Stanford, CA, 94305, USA. kcgarcia@stanford.edu.
