Aberrant follicular regulatory T cells associate with immunoglobulin hyperproduction in nasal polyps with ectopic lymphoid tissues.

Abstract

Ectopic lymphoid tissues (eLTs) and associated follicular helper T (T_FH) cells contribute to local immunoglobulin hyperproduction in nasal polyps (NPs). Follicular regulatory T (T_FR) cells in secondary lymphoid organs counteract T_FH cells and suppress immunoglobulin production; however, the presence and function of T_FR cells in eLTs in peripheral diseased tissues remain poorly understood. We sought to investigate the presence, phenotype, and function of T_FR cells in NPs. The presence, abundance, and phenotype of T_FR cells in NPs were examined using single-cell RNA sequencing, immunofluorescence staining, and flow cytometry. Sorted polyp and circulating T-cell subsets were cocultured with autologous circulating naïve B cells, and cytokine and immunoglobulin production were measured by ELISA. T_FR cells were primarily localized within eLTs in NPs. T_FR cell frequency and T_FR cell/T_FH cell ratio were decreased in NPs with eLTs compared with NPs without eLTs and control inferior turbinate tissues. T_FR cells displayed an overlapping phenotype with T_FH cells and FOXP3⁺ regulatory T cells in NPs. Polyp T_FR cells had reduced CTLA-4 expression and decreased capacity to inhibit T_FH cell-induced immunoglobulin production compared with their counterpart in blood and tonsils. Blocking CTLA-4 abolished the suppressive effect of T_FR cells. Lower vitamin D receptor expression was observed on polyp T_FR cells compared with T_FR cells in blood and tonsils. Vitamin D treatment upregulated CTLA-4 expression on polyp T_FR cells and restored their suppressive function in vitro. Polyp T_FR cells in eLTs have decreased CLTA-4 and vitamin D receptor expression and impaired capacity to suppress T_FH cell-induced immunoglobulin production, which can be reversed by vitamin D treatment in vitro.