Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma

• Published in: Nature communications Vol. 8; no. 1; p. 14937
• Main Authors: Verstraete, Kenneth, Peelman, Frank, Braun, Harald, Lopez, Juan, Van Rompaey, Dries, Dansercoer, Ann, Vandenberghe, Isabel, Pauwels, Kris, Tavernier, Jan, Lambrecht, Bart N., Hammad, Hamida, De Winter, Hans, Beyaert, Rudi, Lippens, Guy, Savvides, Savvas N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.04.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/31; 631/154/51/2314; 631/250/256; 631/45/127; 631/535/1266; 631/57/2272/1590; 82; 82/16; 82/58; 82/6; 82/83; Allergies; Antibodies, Monoclonal - pharmacology; Asthma; Asthma - immunology; Asthma - pathology; Biochemistry; Biology; Chemokines - biosynthesis; Chronic obstructive pulmonary disease; Crystallography, X-Ray; Cytokines; Cytokines - antagonists & inhibitors; Cytokines - chemistry; Dendritic Cells; Dermatitis; HEK293 Cells; Human health and pathology; Humanities and Social Sciences; Humans; Hydrophobic and Hydrophilic Interactions; Hypersensitivity - immunology; Hypersensitivity - pathology; Life Sciences; Models, Molecular; Monoclonal antibodies; multidisciplinary; Multiprotein Complexes - metabolism; Pathophysiology; Protein Structure, Secondary; Receptors, Cytokine - chemistry; Receptors, Cytokine - metabolism; Receptors, Interleukin-7 - chemistry; Receptors, Interleukin-7 - metabolism; Recombinant Fusion Proteins - metabolism; Science; Science (multidisciplinary); Signal Transduction; Belgium; France; allergie; pathophysiologie; allergy; bronchial asthma; skin disease; cytokine anti inflammatoire; asthme; dermatite
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14937

The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma and atopic dermatitis. The emergence of human TSLP as a clinical target against asthma calls for maximally harnessing its therapeutic potential via structural and mechanistic considerations. Here we employ an integrative experimental approach focusing on productive and antagonized TSLP complexes and free cytokine. We reveal how cognate receptor TSLPR allosterically activates TSLP to potentiate the recruitment of the shared interleukin 7 receptor α-chain (IL-7Rα) by leveraging the flexibility, conformational heterogeneity and electrostatics of the cytokine. We further show that the monoclonal antibody Tezepelumab partly exploits these principles to neutralize TSLP activity. Finally, we introduce a fusion protein comprising a tandem of the TSLPR and IL-7Rα extracellular domains, which harnesses the mechanistic intricacies of the TSLP-driven receptor complex to manifest high antagonistic potency. The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is a promising therapeutic target. Here the authors characterize the assembly mechanism of the receptor complex driven by human TSLP, and its antagonism by the monoclonal antibody Tezepelumab and a fusion protein comprising the TSLP receptors.