TY - JOUR
T1 - Oxysterol Gradient Generation by Lymphoid Stromal Cells Guides Activated B Cell Movement during Humoral Responses
AU - Yi, Tangsheng
AU - Wang, Xiaoming
AU - Kelly, Lisa M.
AU - An, Jinping
AU - Xu, Ying
AU - Sailer, Andreas W.
AU - Gustafsson, Jan Ake
AU - Russell, David W.
AU - Cyster, Jason G.
N1 - Funding Information:
We thank R. Brink for providing HEL 2x , M. Tanaka for CD169 DTR mice, R. Lathe for making Cyp7b1 +/− mice available, and M. Barnes and A. Reboldi for comments on the manuscript. T.Y. is an Irvington Institute Postdoctoral Fellow at the Cancer Research Institute, and J.G.C. in an Investigator at the Howard Hughes Medical Institute. This work was supported by National Institutes of Health grants AI40098 and HL20948. A.W.S is a current employee of Novartis and holds stock and stock options in the Novartis company.
PY - 2012/9/21
Y1 - 2012/9/21
N2 - 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.
AB - 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.
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U2 - 10.1016/j.immuni.2012.06.015
DO - 10.1016/j.immuni.2012.06.015
M3 - Article
C2 - 22999953
AN - SCOPUS:84866518376
SN - 1074-7613
VL - 37
SP - 535
EP - 548
JO - Immunity
JF - Immunity
IS - 3
ER -