GPR183

EBI2 helps B cell homing to the outer follicular region within a lymph node. Approximately three hours following B cell exposure to plasma-soluble antigen, EBI2 is upregulated via the transcription factor BRRF1.[6] More surface receptors binding the oxysterol ligand results in cellular migration up the gradient, to the outer follicular region.[8] The reason for this early migration is still unknown; however, because soluble antigen enters lymph nodes via afferent lymphatic vasculature, near the outer region of the follicle, it is hypothesized that B cell movement is motivated by increased exposure to the antigen.[8][6] Six hours after antigen exposure, EBI2 is downregulated to low levels, permitting the B cells to migrate to the border between the B cell and T cell zones of the lymph node. Here, B cells interact with T helper cells previously activated by antigen-presenting dendritic cells. Though CCR7 is the dominant receptor in this stage of B cell migration, EBI2 is still critical, the low expression of which contributes to organized interaction along the T zone border that maximizes interactions with T cells.[8][6] Following B cell receptor and CD40 co-stimulation, EBI2 is again upregulated.[13] The B cells thus move back toward the outer follicular space, where they begin cell division.[8] At this point, a B cell either downregulates EBI2 expression in order to enter a germinal center or maintains EBI2 expression and remains in outer follicular regions. In germinal centers (GC), B cells downregulate the receptor via the transcriptional repressor B-cell lymphoma-6 (BCL6) and, following somatic hypermutation, differentiate into long-lived antibody-secreting plasma cells or memory B cells. EBI2 must turn off to move B cells to the germinal center from the periphery, and must turn on for B cells to exit the germinal center and re-enter the periphery.[13] Meanwhile, those remaining outside the follicle differentiate into plasmablasts, eventually becoming short-lived plasma cells.[6][8] Thus, EBI2 expression modulates B cell differentiation by directing cells toward or away from germinal centers.

EBI2 also regulates intra-lymphatic T cell migration. Mature T helper cells upregulate EBI2 to follow the oxysterol gradient, migrating to the outer edges of the T cell zone to receive signals from antigen-presenting dendritic cells arriving from the tissues.[6] This migration is critical as the resulting T cell-DC interaction induces T helper cell differentiation into T follicular helper cells.[14] In concert with upregulation of CXCR5, the downregulation of EBI2 helps T follicular helper cells move toward the follicle center to help B cells undergoing affinity maturation in germinal centers.[6]

EBI2 expression on CD4+ dendritic cells is a key initiator of immune response. Antigen-activated dendritic cells are driven to lymph node bridging channels via the oxysterol-EBI2 pathway.[9] In the spleen, bridging channels connect the marginal zone, where dendritic cells pick up plasma-soluble antigen, to the T cell zone, where they present antigen to T helper cells. This results in T cell proliferation and differentiation.[6] Localization to bridging channels is also associated with dendritic cell reception of lymphotoxin beta signaling, which augments their blood pathogen uptake, resulting in an increase in T cell responses.[7]