Selective ablation of follicular dendritic cells in mice results in disorganization of primary follicles and dispersal of B cells out of splenic germinal centers.
Summary
7α,25-dihydroxycholesterol (7α,25-OHC) is a ligand for the G-protein coupled receptor EBI2 (GPR183); however, the cellular sources of this oxysterol are undefined. 7α,25-OHC is synthesized from cholesterol by the stepwise actions of two enzymes, CH25H and CYP7B1, and is metabolized to a 3-oxo derivative by HSD3B7. We show that all three enzymes control EBI2-ligand concentration in lymphoid tissues. Lymphoid stromal cells are the main CH25H and CYP7B1-expressing cells required for positioning of B cells and they also mediate 7α,25-OHC inactivation. CH25H and CYP7B1 are abundant at the follicle perimeter whereas CH25H expression by follicular dendritic cells is repressed. CYP7B1-, CH25H- and HSD3B7-deficiencies each result in defective T-cell dependent plasma cell responses. These findings establish that CYP7B1 and HSD3B7, as well as CH25H, have essential roles in controlling oxysterol production in lymphoid tissues and they suggest that differential enzyme expression in stromal cell subsets establishes 7α,25-OHC gradients required for B cell responses.
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