title: Oxysterol gradient generation by lymphoid stromal cells guides activated B cell movement during humoral responses.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.
authors.forename: Tangsheng
authors.initials: T
authors.lastname: Yi
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Kelly
authors.forename: Jinping
authors.initials: J
authors.lastname: An
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Sailer
authors.forename: Jan-Ake
authors.initials: JA
authors.lastname: Gustafsson
authors.forename: David W
authors.initials: DW
authors.lastname: Russell
authors.forename: Jason G
authors.initials: JG
authors.lastname: Cyster
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D000072474:Cytochrome P450 Family 7; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D006888:Hydroxycholesterols / Q000276:immunology* / Q000378:metabolism; D056724:Immunity, Humoral / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017154:Stromal Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: C543809:Gpr183 protein, mouse; D006888:Hydroxycholesterols; D043562:Receptors, G-Protein-Coupled; C057657:7,25-dihydroxycholesterol; D015096:3-Hydroxysteroid Dehydrogenases; C066485:3 beta-hydroxy-delta 5-C(27)-steroid dehydrogenase; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C097207:Cyp7b1 protein, mouse; C507384:cholesterol 25-hydroxylase