Optimal human pathogenic TH2 cell effector function requires local epithelial cytokine signaling

Background: 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 TH2 cells, but its role in T-cell effector function has not been elucidated. Objective: 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. Methods: 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. Results: ST2 expression on peripheral allergen-specific CD4(+) T cells was confined to subjects with allergy and restricted to T(H)2A cells. Comparison between direct peptide major histocompatibility complex class II tetramer staining and the CD154 functional assay identified ST2 as a marker of T(H)2A cell activation. IL-33 exposure enhanced IL-4 and IL-5 secretion in allergen-reactive T(H)2A cells. Allergen induced ST2 expression on peripheral CD4(+) T cells can be used to track allergen-reactive T(H)2A cells from donors with allergy. Conclusion: ST2 expression on circulating CD41 T cells represents a transient phenotype associated with T(H)2A cell activation, allowing these cells to sense locally elicited tissue cytokines. IL-33 selectively amplifies pathogenic T(H)2 cell effector functions, suggesting a tissue checkpoint that may regulate adaptive allergic immunity.