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

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.
Immunity (Impact Factor: 19.75). 09/2012; 37(3):535–548. DOI: 10.1016/j.immuni.2012.06.015

ABSTRACT 7 alpha,25-dihydroxycholesterol (7 alpha,25-OHC) is a ligand for the G protein-coupled receptor EBI2; however, the cellular sources of this oxysterol are undefined. 7 alpha,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 7 alpha,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 7 alpha,25-OHC gradients required for B cell responses.

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    • "EBI2 expression has been well characterized for B cells, where differential expression of EBI2 during B cell maturation is a key regulator of B cell positioning in lymphoid follicles, collaborating with other B cell-expressed chemokine receptors including CXCR5 and CCR7 [24], [25], [30]. The migration of B cells is dictated by the oxysterol 7α,25-dihydroxycholesterol (7α,25-OHC) [26], [27], [31], thereby ascribing EBI2 with a functional role as a chemotactic receptor. Moreover, EBI2 is required for positioning splenic CD4+ DC into bridging channels within germinal centers, which may promote sampling of systemic, particulate antigens [28], [29]. "
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    • "Moreover, recent studies reveal additional complexity. In­ deed, other cells of the microenvironment have been reported to express oxysterol­producing enzymes and to generate oxysterols (Diczfalusy et al., 2009; Yi et al., 2012). Because tumor microenvironment is a complex tissue, in which all the cells described so far to generate oxysterols are present (tumor cells, stromal cells, and immune cells), we speculate that appropriate mouse models are needed to investigate the rela­ tive contribution of oxysterol­producing cells within tumors. "
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    • "During a T cell dependent antibody response the engagement of the B cell antigen receptor by cognate antigen initiates an activation program that prepares naïve B cells to receive T cell help [1] One consequence is an increase in their sensitivity to CCR7 and EBI2 ligands, which helps localize the recently antigen activated B cells to the T-B cell border and interfollicular zones, the sites where they receive T cell help and undergo an initial proliferative expansion [2], [3], [4]. These expanding B cells have three fates: an early plasmablast, which is responsible for the initial extra-follicular antibody response; an early memory B cell; or a GC precursor [1]. "
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