Trained immunity and tolerance in innate lymphoid cells, monocytes, and dendritic cells during allergen-specific immunotherapy.

Abstract Background Despite efficacy of allergen-specific immunotherapy (AIT), the role of trained immunity and tolerance in this process has not been elucidated. Objective Here, we performed a comprehensive, longitudinal analysis of systemic innate immune cell repertoire in the course of AIT. Methods Allergic patients received standard preseasonal subcutaneous AIT with allergoids to birch and/or grass. Healthy controls were monitored without any intervention. Flow cytometry of ILC, NK, monocyte, and DC subsets was performed at baseline, 3 months (birch season), 6 months (grass seasons), and 12 months after the therapy in patients or in similar seasonal time points in controls. Additional analyses were performed in the 3rd-year birch and grass season. Results We observed a durable decrease of ILC2 and an increase of ILC1 after AIT with dynamic changes in their composition. We found that an expansion of CD127+CD25++ clusters caused observed shifts in ILC1 heterogeneity. In addition, we observed development of CD127+CD25++c-Kit+ ILC3 clusters. Moreover, we found an increase in intermediate monocytes, in parallel to the reduction of non-classical monocytes during first year after AIT. Classical and intermediate monocytes presented significant heterogeneity in allergic patients, but AIT reduced HLA-DR++ clusters. Finally, an increase in pDCs and CD141+ mDCs was observed in allergic individuals, while CD1c+ mDCs were reduced during 1st year of AIT. Conclusion AIT induces changes in the composition and heterogeneity of circulating innate immune cells and brings them to the level observed in healthy individuals. Monitoring of ILC, monocytes, and DCs during AIT might serve as a novel biomarker strategy.