IL-33 is an emerging key factor in development of allergic diseases. The IL-33 receptor (suppressor of tumorigenicity [ST2]) is a differentially expressed gene in pathogenic T_H2 cells, but its role in T-cell effector function has not been elucidated.

We investigated the role of IL-33 in modulating circulating allergen-specific T-cell responses. We hypothesized that selective ST2 expression on allergen-specific CD4⁺ T cells would confer susceptibility to the effects of IL-33.

PBMCs from subjects with food allergy, inhalant allergy, and no allergy were obtained on the basis of clinical history and serum IgE level. A T-cell receptor–dependent CD154 upregulation assay and direct peptide major histocompatibility complex class II tetramer staining were used to profile allergen-specific CD4⁺ T cells by flow cytometry. Allergen-specific CD4⁺ T cell cytokine production was evaluated during IL-33 exposure. ST2 expression was also tracked by using a 2-color flow-based assay.

ST2 expression on peripheral allergen-specific CD4⁺ T cells was confined to subjects with allergy and restricted to T_H2A cells. Comparison between direct peptide major histocompatibility complex class II tetramer staining and the CD154 functional assay identified ST2 as a marker of T_H2A cell activation. IL-33 exposure enhanced IL-4 and IL-5 secretion in allergen-reactive T_H2A cells. Allergen-induced ST2 expression on peripheral CD4⁺ T cells can be used to track allergen-reactive T_H2A cells from donors with allergy.

ST2 expression on circulating CD4⁺ T cells represents a transient phenotype associated with T_H2A cell activation, allowing these cells to sense locally elicited tissue cytokines. IL-33 selectively amplifies pathogenic T_H2 cell effector functions, suggesting a tissue checkpoint that may regulate adaptive allergic immunity.