Tezepelumab Reverses TSLP-Driven Immunometabolic Rewiring in Human cDC2s Underlying Pathogenic Th2 and Dysfunctional Treg Responses.

Abstract

Thymic stromal lymphopoietin (TSLP) is a key epithelial alarmin involved in the initiation and maintenance of type 2 inflammatory airway diseases. Although tezepelumab, the first approved anti-TSLP monoclonal antibody, has shown robust clinical efficacy in asthma and CRSwNP, the molecular mechanisms underlying its mode of action remain incompletely defined. To determine whether TSLP induces a pathogenic immunometabolic program in human type 2 conventional dendritic cells (cDC2s) and whether tezepelumab can directly reverse this process. Purified human circulating cDC2s from healthy non-atopic donors were stimulated with TSLP in the presence or absence of tezepelumab. cDC2 phenotype, function, metabolism, and T-cell polarization capacity were assessed. Pathogenic Th2 responses, Treg generation, suppressive function, and metabolic fitness were analyzed. TSLP induced a metabolic rewiring in human cDC2s characterized by increased glycolysis and mitochondrial oxidative phosphorylation. This metabolic hyperactivation was associated with the acquisition of a pro-type 2 phenotype and required for the induction of pathogenic T-cell responses. TSLP-activated cDC2s generated pathogenic Th2 cells and FOXP3⁺ Tregs with impaired suppressive function and an altered metabolic profile. Tezepelumab effectively reversed TSLP-induced metabolic and functional reprogramming in cDC2s, thereby limiting pathogenic Th2 polarization while restoring the functional and metabolic properties of induced Tregs. We identify immunometabolic rewiring as a key mechanism of the TSLP-cDC2 axis and provide mechanistic insight into how tezepelumab reshapes pathogenic adaptive immune responses. These results support upstream epithelial alarmin blockade as a strategy to interfere with early disease-driving immune programs in type 2 inflammatory airway diseases.