<scp>TNF</scp> Pathway‐Mediated Tolerogenic T‐Cell Trajectory Driven by Allergen Immunotherapy

BACKGROUND: Allergen immunotherapy (AIT) is a therapeutic approach to restore allergen tolerance and prevent asthma progression. Previous studies have shown exhaustion of T cells and the induction of T cells expressing IL-17 and FOXP3 early in AIT, which are relevant for the clinical outcome. This study aims to investigate the dynamic transition from type-3 immunity to a regulatory state observed in the first year during allergic inflammation, as well as the subsequent dysfunction of effector cells during AIT. METHODS: Human and experimental models of allergic airway inflammation were used to assess the impact of AIT on Treg, Tr17 and Th17 cell populations using flow cytometry and proliferation assays. Additionally, human blood samples were analysed using single-cell transcriptomics to characterise transcriptional signatures associated with the transition from pro-inflammatory to regulatory states. RESULTS: AIT restored balance of Tr17 and Treg populations and increased their proliferative capacity, whereas Th17 cells remained functionally impaired. Single-cell transcriptomics identified Tr17 cells as intermediate states between pro-inflammatory and regulatory T-cell programs after AIT. In parallel, AIT reprogrammed intracellular communication networks, with TNF/LTA-associated signalling pathways emerging as prominent mediators of tolerogenic signalling. CONCLUSION: These findings highlight that AIT reprograms immune responses by enhancing regulatory dominance, inducing Tr17 plasticity and leveraging TNF/TNFR2-mediated tolerance. Understanding the cellular dynamics during AIT suggests that therapeutic strategies aimed at targeting Th17 functional impairment could further enhance treatment efficacy for allergic airway diseases. This insight opens new avenues for refining immunotherapeutic approaches to more effectively restore immune balance and improve patient outcomes.