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

Abstract

BACKGROUND\nIL-33 is an emerging key factor in development of allergic diseases. The IL-33 receptor (ST2) is a differentially expressed gene in pathogenic TH2 cells but its role in T cell effector function has not been elucidated.\n\n\nOBJECTIVE\nWe investigated the role of IL-33 in modulating circulating allergen-specific T cell responses. We hypothesized selective ST2 expression on allergen-specific CD4+ T cells would confer susceptibility to the effects of IL-33.\n\n\nMETHODS\nPBMCs from food allergic, inhalant allergic, and non-allergic subjects were obtained based on clinical history and serum IgE. A T cell receptor (TCR) dependent CD154 up-regulation assay and direct peptide-major histocompatibility complex class II (pMHC-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 using a two-color flow-based assay.\n\n\nRESULTS\nST2 expression on peripheral allergen-specific CD4+ T cells was confined to allergic subjects and restricted to TH2A cells. Comparison between direct pMHCII tetramer staining and the CD154 functional assay identified ST2 as a TH2A-activation marker. IL-33 exposure enhanced IL-4 and IL-5 secretion in allergen-reactive TH2A cells. Allergen-induced ST2 expression on peripheral CD4+ T cells can be used to track allergen-reactive TH2A cells from allergic donors.\n\n\nCONCLUSION\nST2 expression on circulating CD4+ T cells represents a transient phenotype associated with TH2A cell activation allowing these cells to sense locally-elicited tissue cytokines. IL-33 selectively amplifies pathogenic TH2 cell effector functions suggesting a tissue checkpoint that may regulate adaptive allergic immunity.