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-1highCXCR5-CD4+ T cells outside lymphoid aggregates was found in NPs. Nasal PD-1highCXCR5-CD4+ T cells were characterized by a unique phenotype that was related to B-cell help and tissue residency and distinct from PD-1-/intCXCR5- and CXCR5+ CD4+ T cells in NPs as well as PD-1highCXCR5highCD4+ follicular helper T cells in tonsils. Compared with the frequencies of PD-1highCXCR5-CD4+ T cells and their IFN-γ+, 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-1highCXCR5-CD4+ T cells induced immunoglobulin production from B cells in a potency comparable to that induced by tonsillar follicular helper T cells. PD-1highCXCR5-CD4+ T-cell frequencies were correlated with IgE levels in eosinophilic NPs. PD-L1 and PD-L2 suppressed the function of PD-1highCXCR5-CD4+ T cells, and their levels were reduced in NPs. PD-1highCXCR5-CD4+ T-cell abundance was associated with the postsurgical relapse of NPs. CONCLUSION: PD-1highCXCR5-CD4+ T cells participate in local immunoglobulin production independent of eLTs in NPs.

Synthesis and cytotoxicity of racemic isodeoxypodophyllotoxin analogues with isoprene-derived side chains.

A series of isodeoxypodophyllotoxin (5) analogues, 26-38, with various isoprene-derived side chains at the E-ring were designed and synthesized. For comparison, compound 39, with a benzyloxy group on the E-ring, and six D-ring opened analogues, 40-45, were also prepared. All the synthetic compounds were evaluated for their cytotoxic activities in vitro against seven cultured human tumor cell lines. Compounds 27, 43, and 44 were more cytotoxic than etoposide on BEL-7404, A549, and HL-60 cell lines, respectively. However, none of the synthetic isodeoxypodophyllotoxins were more cytotoxic than podophyllotoxin (1).