Guidance of B Cells by the Orphan G Protein-Coupled Receptor EBI2 Shapes Humoral Immune Responses

Abstract

Humoral immunity depends on both rapid and long-term antibody production against invading pathogens. This is achieved by the generation of spatially distinct extrafollicular plasmablast and follicular germinal center (GC) B cell populations, but the signals that guide responding B cells to these alternative compartments have not been fully elucidated. Here, we show that expression of the orphan G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) by activated B cells was essential for their movement to extrafollicular sites and induction of early plasmablast responses. Conversely, downregulation of EBI2 enabled B cells to access the center of follicles and promoted efficient GC formation. EBI2 therefore provides a previously uncharacterized dimension to B cell migration that is crucial for coordinating rapid versus long-term antibody responses.

Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis

“…However, systemic RANKL administration has been shown to increase OCP homing back to BM and to promote local OC differentiation (Kotani et al, 2013). These studies suggest that OCP movement in and out of BM tissue is highly regulated and that balanced responsiveness to B lymphocyte migration in secondary lymphoid organs (Gatto et al, 2009(Gatto et al, , 2013Pereira et al, 2009b;Hannedouche et al, 2011;Kelly et al, 2011;Liu et al, 2011;Yi and Cyster, 2013), in controlling monocyte and OCP movement and positioning within BM. We show that EBI2 is highly expressed in OCPs and mature OCs and promotes OCP motility in vitro and in various chemoattractants regulates OCP movement and differentiation.…”

“…EBI2 and its oxysterol ligands control immune cell migration (Gatto et al, 2009;Pereira et al, 2009bPereira et al, , 2010aHannedouche et al, 2011;Liu et al, 2011). We hypothesized that EBI2 promotes BMDM and OCP migration, thereby influencing cell-cell interaction and cell fusion.…”

Plasma cells in systemic lupus erythematosus: The long and short of it all

“…Although extrafollicular B cells do not undergo extensive somatic mutation, they may still secrete pathogenic autoantibodies [12,13]. Plasma cells derived from the extrafollicular focus are dependent on BAFF and a proliferationinducing ligand (APRIL) for their immediate survival but they are short-lived, surviving an average of 3-4 days [11,16].B cells with relatively low affinity tend to enter germinal centers; this is mediated through downregulation of EBI2 [14]. Subsequent differentiation into either memory or plasma cells is regulated in part by the strength of the BCR signal [17].…”

“…B cells with intrinsically higher affinity preferentially migrate to the extrafollicular focus where they rapidly expand and become plasma cells that secrete a first wave of protective antibodies [10,11]. Migration to the extrafollicular focus requires expression of the adhesion molecule Epstein-Barr virus induced molecule-2 (EBI2) and is enhanced by strong costimulatory signals, TLR9 ligation, and exposure to IL-12 [12][13][14][15]. This is particularly relevant to SLE because autoreactive B cells that recognize and internalize DNA activate TLR9 and may also be exposed to excessive CD40-mediated signals and cytokines.…”

“…B cells with relatively low affinity tend to enter germinal centers; this is mediated through downregulation of EBI2 [14]. Subsequent differentiation into either memory or plasma cells is regulated in part by the strength of the BCR signal [17].…”