Immunity 37, 535–548 (2012)

B cells of the immune system follow a defined path through secondary lymphoid organs that culminates in interactions with T cells and movement to inter- and outerfollicular regions of the spleen that are required for an efficient antibody response. EBI2 is a G protein–coupled receptor that guides B cells during this process. To define the molecular basis of these movements, Yi et al. monitored the activities and localizations of the biosynthetic enzymes involved in generation and metabolism of the EBI2 ligand, 7α,25-dihydrocholesterol (7α,25-OHC). Using flow cytometry, real-time PCR on follicular cells and selective ablation of follicular dendritic cells, the authors found that the two enzymes responsible for generation of 7α,25-OHC from cholesterol, CH25H and CYP7B1, along with the enzyme that degrades 7α,25-OHC, HSD3B7, are all required for a humoral immune response. In a first clue that spatial organization is important in this response, the authors find that the sequential action of CH25H and CYP7B1 do not necessarily occur within the same cells. Also, the biosynthesis of 7α,25-OHC is highest in outer follicular regions, including stromal cells, in the T zone and at the B-cell zone–T-cell zone (B-T) boundary, whereas degradation is greatest in the T zone. These actions mirror the sequential movement of B cells from follicles to the B-T boundary, where they are activated through to the interfollicular and outer follicular regions, suggesting that a ligand gradient guides the movements of naive and activated B cells.