Understanding the mechanisms by which the immune system induces and controls allergic inflammation at the T-cell epitope level is critical for the design of new allergy vaccine strategies.

We sought to characterize allergen-specific T-cell responses linked with allergy or peripheral tolerance and to determine how CD4⁺ T-cell responses to individual allergen-derived epitopes change over allergen-specific immunotherapy.

Timothy grass pollen (TGP) allergy was used as a model for studying grass pollen allergies. The breadth, magnitude, epitope hierarchy, and phenotype of the DR04:01-restricted TGP-specific T-cell responses in 10 subjects with grass pollen allergy, 5 nonatopic subjects, and 6 allergy vaccine–treated subjects was determined by using an ex vivo peptide–MHC class II tetramer approach.

CD4⁺ T cells in allergic subjects are directed to a broad range of TGP epitopes characterized by defined immunodominance hierarchy patterns and with distinct functional profiles that depend on the epitope recognized. Epitopes that are restricted specifically to either T_H2 or T_H1/T_R1 responses were identified. Allergen-specific immunotherapy was associated with preferential deletion of allergen-specific T_H2 cells and without a significant change in the frequency of T_H1/T_R1 cells.

Preferential allergen-specific T_H2 cell deletion after repeated high-dose antigen stimulation can be another independent mechanism to restore tolerance to allergen during immunotherapy.