Human Follicular Dendritic Cells Interact with T Cells via Expression and Regulation of Cyclooxygenases and Prostaglandin E and I Synthases

Abstract

PGE2 inhibits mature T cell proliferation and protects T cells from activation-induced cell death (AICD). We have previously demonstrated that human follicular dendritic cells (FDC) strongly express PGI synthase. In this study, the hypothesis that FDC have regulatory roles on germinal center T cells by controlling production of PGE2 and PGI2 was tested. Confocal microscopic analyses of human tonsil tissues revealed that FDC indeed expressed PGE synthase in addition to PGIS. To confirm these results, we studied the regulation mechanism of PG production in FDC, using an established human FDC-like cell line, HK. Specifically in response to TNF-α, TGF-β, and LPS, protein expression of cyclooxygenase (COX)-2 and downstream PGE synthase was up-regulated with coordinate kinetics, whereas COX-1 and PGIS were constitutively expressed. The increase of these enzymes was reflected in actual production of PGE2 and PGI2. Interestingly, IL-4 almost completely abrogated the stimulatory activity of TNF-α, TGF-β, and LPS in PG production. Furthermore, the up-regulation of PGE2 and PGI2 production was markedly down-regulated by indomethacin and a selective COX-2 inhibitor. PGI2 analog and PGE2 inhibited proliferation and AICD of T cells in dose- and time-dependent manners. Finally, coculture experiments revealed that HK cells indeed inhibit proliferation and AICD of T cells. Put together, these results show an unrecognized pathway of FDC and T cell interactions and differential mechanisms for PGE2 and PGI2 production, suggesting an important implication for development and use of anti-inflammatory drugs.

Beraprost Enhances the APC Function of B Cells by Upregulating CD86 Expression Levels

“…Because B cells were incubated with beraprost before the further culture with T cells, one may suspect that the residual beraprost might have influenced the enhanced proliferation. This is unlikely according to our previous results that showed a suppression of T cell proliferation by beraprost (11,39). Considering the fact that GC T cells do not normally proliferate and produce IL-2 in response to Ag stimulation (40)(41)(42), there must be a balance between positive and negative signals for cellular proliferation.…”

“…Considering the fact that GC T cells do not normally proliferate and produce IL-2 in response to Ag stimulation (40)(41)(42), there must be a balance between positive and negative signals for cellular proliferation. In this balance control, FDCs appear to have a dominating role by providing prostacyclin and PGE 2 (11).…”

“…We found that PGE 2 synthase in addition to PGIS was expressed in the GC (11). Therefore, we examined whether PGE 2 as well as beraprost might regulate CD54 and CD86 expression levels on activated B cells.…”

“…We have recently reported that prostacyclin synthase (PGIS) is expressed in the GC and that FDC-like cells produce prostacyclin (11). Because FDCs are known to regulate important functions of B cells in the GC, we investigated whether prostacyclin modulates the APC function of B cells.…”

IL-21–Dependent B Cell Death Driven by Prostaglandin E2, a Product Secreted from Follicular Dendritic Cells

“…FDCs accumulate administered Ags on their surface in the form of immune complexes, which act as selection ligands for GC B cells bearing diversified BCRs. Additionally, it has been reported that our FDC line (20), human FDC lines established by other laboratories (39), and FDCs isolated from lymphoid tissues (40) all expressed PGE synthase. Thus, PGE 2 production is considered to be a characteristic feature of FDCs.…”