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.