title: IL-21-dependent B cell death driven by prostaglandin E2, a product secreted from follicular dendritic cells.
abstract: In germinal centers (GCs), B cells are selected through interaction with follicular dendritic cells bearing immune complexes and follicular helper T (Tfh) cells secreting Tfh cytokines, including IL-21. To analyze these cellular interactions, we have explored culture conditions that can simulate GC B cell selection in vitro using a mouse follicular dendritic cell line, FL-YB. FL-YB cells efficiently enhanced viability of cocultured mouse B cells in a BAFF-dependent fashion. Interestingly, we found that addition of IL-21, a major Tfh cytokine, readily induced death of B cells that were cocultured with FL-YB cells, whereas IL-21 alone sustained viability of B cells in the absence of FL-YB cells. The IL-21-induced death was dependent on a low m.w. soluble factor that was released from FL-YB cells, which was finally identified as PGE(2). Treatment of B cells with IL-21 plus PGE(2), but not either alone, resulted in enhanced expression of a proapoptotic protein Bim and the upstream transcription factor Foxo1. A PGE(2) receptor isoform, EP4, was responsible for IL-21/PGE(2)-induced B cell death. Thus, PGE(2) is an endogenous chemical mediator that can switch pleiotropic actions of IL-21 on B cells. IL-21/PGE(2)-induced B cell death was rescued if B cells were costimulated via CD40. In immunized mice, deficiency of IL-21R in B cells led to a significant decrease in the frequency of activated caspase-3-positive GC B cells concomitant with impaired affinity maturation of Abs. Taken together, results implicate a physiological role of IL-21/PGE(2)-induced B cell death in GC B cell selection.
authors.affiliation: Department of Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Magari
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Nishikawa
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Fujii
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nishio
authors.forename: Koji
authors.initials: K
authors.lastname: Watanabe
authors.forename: Michiya
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Naoki
authors.initials: N
authors.lastname: Kanayama
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ohmori
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D002469:Cell Separation; D018920:Coculture Techniques; D020566:Dendritic Cells, Follicular / Q000276:immunology / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D005434:Flow Cytometry; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D015232:Dinoprostone; D000098546:Interleukin-21