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

By K. Verstraete, F. Peelman, H. Braun, Juan Lopez, Dries Van Rompaey, A. Dansercoer, I. Vandenberghe, K. Pauwels, J. Tavernier, B. Lambrecht and 5 more. 2017

171 citations recorded by the source corpus.

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.

Subfields: Dermatology, Immunology and Allergy, Physiology

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Citations in the corpus

Modulation of Signaling Mediated by TSLP and IL-7 in Inflammation, Autoimmune Diseases, and Cancer (2020, background): “In the same time, the other side of TSLP helical bundle involved in binding IL-7Rα remains available (82) (Figure 4A).”
Structural activation of pro-inflammatory human cytokine IL-23 by cognate IL-23 receptor enables recruitment of the shared receptor IL-12Rβ1 (2017, background): “…increase in affinity of IL-12R β 1 to the IL-23:IL-23R complex, it does not appear to involve extensive receptor-receptor interactions between the extracellular domains of the two receptors contrary to other cytokine receptors (Felix et al., 2015; Spangler et al., 2015; Verstraete et al., 2017).”