Immunity
Volume 37, Issue 3, 21 September 2012, Pages 535-548
Journal home page for Immunity

Article
Oxysterol Gradient Generation by Lymphoid Stromal Cells Guides Activated B Cell Movement during Humoral Responses

https://doi.org/10.1016/j.immuni.2012.06.015Get rights and content
Under an Elsevier user license
open archive

Summary

7α,25-dihydroxycholesterol (7α,25-OHC) is a ligand for the G protein-coupled receptor EBI2; 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 showed that all three enzymes control EBI2 ligand concentration in lymphoid tissues. Lymphoid stromal cells were the main CH25H- and CYP7B1-expressing cells required for positioning of B cells, and they also mediated 7α,25-OHC inactivation. CH25H and CYP7B1 were abundant at the follicle perimeter, whereas CH25H expression by follicular dendritic cells was repressed. CYP7B1, CH25H, and HSD3B7 deficiencies each resulted 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.

Highlights

► Bile acid enzyme CYP7B1 is required for EBI2 ligand generation and B cell responses ► HSD3B7 inactivates EBI2 ligand and is required in stromal cells for gradient generation ► FDCs are required for EBI2-dependent B cell segregation in the follicle ► HSD3B7 restricts EBI2 ligand production by T zone dendritic cells

Cited by (0)