From inflammation to tolerance
Allergic airway disease is driven by an imbalanced immune response. Certain T cells promote inflammation, while regulatory T cells act as a brake to keep immune reactions under control. Earlier studies had already shown that, early during AIT, many T cells become functionally exhausted and that IL-17- and FOXP3-co-expressing regulatory T cells (Tr17 cells) play a role in clinical improvement.
The DZL team wanted to understand this process in more detail. In particular, they focused on how the immune system shifts from a pro‑inflammatory, so‑called type‑3 immune response towards a more regulatory state, and why some effector cells remain dysfunctional despite treatment.
Studying immune cells in patients and models
To address these questions, the researchers combined human data with experimental models of allergic airway inflammation. They analysed different T‑cell populations, including regulatory T cells (Treg), IL‑17‑producing regulatory T cells (Tr17), and pro‑inflammatory Th17 cells.
Using flow cytometry and proliferation assays, they assessed how these cells respond to AIT over time. In parallel, blood samples from patients were examined with single‑cell transcriptomics. This approach allowed the scientists to study gene expression patterns in individual immune cells and to track subtle changes in cell states during therapy.
Regulatory cells regain strength
The results show a clear shift in immune balance during AIT. Treatment restored the balance between Tr17 cells and classical regulatory T cells and increased their ability to proliferate. In simple terms, regulatory T-cell populations regained proliferative and functional capacity.
In contrast, Th17 cells, which are typically associated with tissue inflammation, remained functionally impaired. Rather than being fully reactivated, these cells seemed to stay in a subdued state, which may be beneficial in the context of allergic disease.
Single‑cell analyses added an important layer of understanding. Importantly, the analyses identified TNF/LTA-associated signalling pathways and TNFR2-mediated communication as key drivers of the tolerogenic immune trajectory induced by AIT. They revealed that Tr17 cells
represent an intermediate state between pro‑inflammatory and regulatory T‑cell programs. After AIT, these cells showed a mixed transcriptional profile, reflecting their plastic nature and their potential to support immune tolerance.
Implications for future therapies
Taken together, the findings show that AIT does not simply suppress allergic inflammation. Instead, it actively reshapes the immune system. It strengthens regulatory dominance, promotes the plasticity of Tr17 cells, and uses specific signalling pathways to maintain tolerance.
At the same time, the persistent dysfunction of Th17 cells suggests room for improvement. Targeting these cells more directly, while preserving the regulatory environment established by AIT, could further enhance treatment efficacy.
For patients with allergic airway diseases, this research offers hope for more refined and effective immunotherapies in the future. For clinicians and scientists, it provides a clearer map of the cellular changes that underpin successful allergen immunotherapy and opens new avenues to restore immune balance more precisely.