Allergen immunotherapy improves defective follicular regulatory T cells in patients with allergic rhinitis

Background: The function of follicular regulatory T (T_FR) cells, especially in regulating IgE production in patients with allergic diseases, is poorly understood. Objective: We sought to investigate the phenotype, function, and clinical relevance of T_FR cells in patients with allergic rhinitis (AR). Methods: The phenotype and frequency of tonsillar and circulating T_FR cells were characterized by using flow cytometry. T_FR cell function was examined in an assay by coculturing with follicular helper T cells and B cells. The associations between T_FR cells and the clinical features in patients with AR before and after allergen immunotherapy (AIT) were analyzed. Results: T_FR cells were detected in germinal centers of tonsils, but compared with subjects without AR, the frequencies decreased in patients with AR who were allergic to house dust mites. Circulating T_FR cells in blood were phenotypically and numerically correlated with tonsillar T_FR cells, and a reduction of circulating T_FR cells but not total or CXCR5⁻ regulatory T cells was noted in patients with AR compared with healthy control subjects. Moreover, circulating T_FR cells in patients with AR showed a specific defect in suppressing IgE production but were capable of suppressing production of other immunoglobulin types. We identified negative associations of circulating T_FR cell frequencies and function with antigen-specific IgE levels or disease severity in patients with AR. After AIT, the frequencies and function of circulating T_FR cells were improved, which positively associated with disease remission. Conclusion: Impairment in T_FR cells might contribute to aberrant IgE production in patients with AR, and AIT improves defective T_FR cell function. T_FR cells might serve as a potential biomarker to monitor clinical response to AIT.