Extrafollicular PD-1highCXCR5–CD4+ T cells participate in local immunoglobulin production in nasal polyps

Background: Local immunoglobulin hyperproduction is observed in nasal polyps (NPs) with and without ectopic lymphoid tissues (eLTs). Objective: Our aim was to identify the T-cell subsets involved in local immunoglobulin production independent of eLTs in NPs. Methods: The localization, abundance, and phenotype of CD4(+) T-cell subsets were studied by immunofluorescence, flow cytometry, and single cell RNA sequencing. Purified nasal T-cell subsets were cultured with autologous peripheral naive B cells to explore their function. Programmed death ligand 1 and programmed death ligand 2 expression in NPs was investigated by immunofluorescence staining and flow cytometry. Results: Accumulation of PD-1(high) CXCR5(-)CD4(+) T cells outside lymphoid aggregates was found in NPs. Nasal PD-1(high) CXCR5(-)CD4(+) T cells were characterized by a unique phenotype that was related to B-cell help and tissue residency and distinct from PD-1(high)CXCR5(+) and CXCR5(+) CD4(+) T cells in NPs as well as PD-1(high) CXCR5(high) CD4(+) follicular helper T cells in tonsils. Compared with the frequencies of PD-1(high) CXCR5(-)CD4(+) T cells and their IFN-gamma(+), IL-17A(+), and IL-21(+) subsets in the control inferior turbinate tissues, the frequencies of these cells and their subsets were increased in both eosinophilic and noneosinophilic NPs, whereas the frequencies of the IL-4(+) and IL-4(+), IL-21(+) subsets were increased only in eosinophilic NPs. Nasal PD-1(high) CXCR5(-)CD4(+) T cells induced immunoglobulin production from B cells in a potency comparable to that induced by tonsillar follicular helper T cells. PD-1(high) CXCR5(-)CD4(+) T-cell frequencies were correlated with IgE levels in eosinophilic NPs. PD-L1 and PD-L2 suppressed the function of PD-1(high) CXCR5(-)CD4(+) T cells, and their levels were reduced in NPs. PD-1(high) CXCR5(-)CD4(+) T-cell abundance was associated with the postsurgical relapse of NPs. Conclusion: PD-1(high) CXCR5(-)CD4(+) T cells participate in local immunoglobulin production independent of eLTs in NPs.