IL-21-dependent B cell death driven by prostaglandin E2, a product secreted from follicular dendritic cells

Masaki Magari, Yumiko Nishikawa, Yasumasa Fujii, Yumi Nishio, Koji Watanabe, Michiya Fujiwara, Naoki Kanayama, Hitoshi Ohmori

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 PGE2, but not either alone, resulted in enhanced expression of a proapoptotic protein Bim and the upstream transcription factor Foxo1. A PGE2 receptor isoform, EP4, was responsible for IL-21/PGE2-induced B cell death. Thus, PGE2 is an endogenous chemical mediator that can switch pleiotropic actions of IL-21 on B cells. IL-21/PGE2-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.

Original languageEnglish
Pages (from-to)4210-4218
Number of pages9
JournalJournal of Immunology
Volume187
Issue number8
DOIs
Publication statusPublished - Oct 15 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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