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 PGE2. 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/PGE2–induced B cell death in GC B cell selection.

Pro-apoptotic effect of anti-β1-adrenergic receptor antibodies in periodontitis patients

“…In the present study, we showed that activation of β 1 -AR in rat atria by anti-β 1 -AR IgG increased PGE 2 generation. The increase in PGE 2 generationmediated atria apoptosis is similar to that occurring in other tissues and was preceded by iNOS activation with an increase of NO [46][47][48]. The participation of PGE 2 in rat atria apoptosis shows that this cytokine is a modulator of the periodontal β 1 autoantibody stimulation/caspase effect.…”

Germinal center B cell development has distinctly regulated stages completed by disengagement from T cell help

“…We established an in vitro culture system that generates BCL6 int RelB + IRF4 + GC precursors prior to BCL6 hi RelB − IRF4 − GC B cells, recapitulating the in vivo observations. As illustrated in Figure 8A, freshly isolated primary B cells were pulse-stimulated with anti-IgM to mimic in vivo antigen recognition, followed by seeding onto BAFF-expressing FL-YB cells for survival support (Magari et al, 2011). At day 3 of culture, T cell associated stimuli (αCD40 and IL-4/21) were washed away and cells were re-cultured in medium only for an additional half-day before analysis.…”

“…FL-YB expresses comparable levels of B cell activating factor (BAFF) to that of FDCs. It was kindly provided by Dr. Masaki Magari and cultured as described in a previous study (Magari et al, 2011). FL-YB cells were tested to be mycoplasma free and validated to be over-expressing BAFF that supports murine primary B cell survival.…”

Macrophage regulation of B cell proliferation

“…The growth suppressive effect of PGE 2 is mediated via binding EP4, a PGE 2 R and candidate tumor suppressor [37]. CD40-activated B cells resist PGE 2 and have been suggested to serve as APCs for tumor vaccination within the suppressive TME [38–40]. Regardless of the form of B cell stimulation, regulatory mechanisms, mediated by macrophages and dendritic cells, are initiated upon activation (41,42).…”