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

ArticleinImmunity 37(3):535–548 · September 2012with16 Reads
DOI: 10.1016/j.immuni.2012.06.015
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.
    • "EBI2 is a G-protein coupled receptor expressed by cells of the immune system and B cells have been shown to migrate towards concentration gradients of 7a,25HC. The expression of EBI2 is important in the positioning of B cells close to locations where they will encounter antigen in lymphoid organs and is involved in the distribution of B cells into the boundary between B and T cell zones [23,38,39]. Furthermore, mice lacking CH25H cannot produce immune activated 25HC and 7a,25HC and accordingly have reduced humoral immunity. "
    [Show abstract] [Hide abstract] ABSTRACT: Infection remains an important cause of morbidity and mortality. Natural defenses to infection are mediated by intrinsic/innate and adaptive immune responses. While our understanding is considerable it is incomplete and emerging areas of research such as those related to the immune-metabolic axis are only beginning to be appreciated. There is increasing evidence showing a connection between immune signaling and the regulation of sterol and fatty acid metabolism. In particular, metabolic intermediates of cholesterol biosynthesis and its oxidized metabolites (oxysterols) have been shown to regulate adaptive immunity and inflammation and for innate immune signaling to regulate the dynamics of cholesterol synthesis and homeostasis. The side-chain oxidized oxysterols, 25-hydroxycholesterol (25HC) and vitamin D metabolites (vitamin D3 and vitamin D2), are now known to impart physiologically profound effects on immune responses. Macrophages play a frontline role in this process connecting immunity, infection and lipid biology, and collaterally are a central target for infection by a wide range of pathogens including viruses and bacteria, especially intracellular bacteria such as mycobacteria. Clinical manifestations of disease severity in the infected host are likely to pay tribute to perturbations of the metabolic-immune phenomena found in lymphocytes and myeloid cells. Historically and consistent with this notion, vitamin D based oxysterols have had a long association with promoting clinical improvements to patients infected with Mycobacterium tuberculosis. Hence understanding the role of early metabolic mediators of inflammatory responses to infection in particular oxysterols, will aid in the development of urgently needed host directed therapeutic and diagnostic design innovation to combat adverse infection outcomes and antibiotic resistance.
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    • "Approximately 60%–70% of PDPN À LNMC express the integrin a7b1 and include contractile pericytes (Malhotra et al., 2012) while PDPN + LNMC are distinguished into three distinct subsets; fibroblastic reticular cells (FRC), follicular dendritic cells (FDC), and marginal reticular cells (MRC). FRC wrap around the reticular network of ERTR7 + collagen-rich fibers in the LN paracortex and contain cells expressing CCR7 ligands (CCL19 and CCL21), IL-7, cholesterol 25-hydroxylase, and B cell activating factor (BAFF) and have been implicated in supporting the homing/migration/survival of T cells (Chang and Turley, 2015; Girard et al., 2012; Link et al., 2007; Yi et al., 2012). In contrast to FRC, FDC and MRC express high protein levels of CXCL13 (Katakai et al., 2008 ). "
    [Show abstract] [Hide abstract] ABSTRACT: Despite the key role of primary and secondary lymphoid organ stroma in immunity, our understanding of the heterogeneity and ontogeny of these cells remains limited. Here, we identify a functionally distinct subset of BP3(-)PDPN(+)PDGFRβ(+)/α(+)CD34(+) stromal adventitial cells in both lymph nodes (LNs) and thymus that is located within the vascular niche surrounding PDPN(-)PDGFRβ(+)/α(-)Esam-1(+)ITGA7(+) pericytes. CD34(+) adventitial cells developed in late embryonic thymus and in postnatal LNs and in the thymus originated, along with pericytes, from a common anlage-seeding progenitor population. Using lymphoid organ re-aggregate grafts, we demonstrate that adult CD34(+) adventitial cells are capable of differentiating into multiple lymphoid stroma-like subsets including pericyte-, FRC-, MRC-, and FDC-like cells, the development of which was lymphoid environment-dependent. These findings extend the current understanding of lymphoid mesenchymal cell heterogeneity and highlight a role of the CD34(+) adventitia as a potential ubiquitous source of lymphoid stromal precursors in postnatal tissues.
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    • "In addition, Hannedouche et al. (2011) further showed that, as a functional consequence, plasma cell response in Ch25H KO mice was similarly defective as that in Ebi2-deficient mice. A subsequent study by Yi et al. (2012) suggested that lymphoid stromal cells were the main Ch25H-and Cyp7B1-expressing cells and were responsible for production of 7α, 25-OHC in vivo. In addition, the group also demonstrated that the same cells were likely also responsible for degradation of 7α, 25-OHC by expressing HSD3B7 which converts 7α, 25-OHC into a 3-oxo derivative. "
    [Show abstract] [Hide abstract] ABSTRACT: EBI2, aka GPR183, is a G-couple receptor originally identified in 1993 as one of main genes induced in Burkitt's lymphoma cell line BL41 by Epstein-Barr virus (EBV) infection. After it was reported in 2009 that the receptor played a key role in regulating B cell migration and responses, we initiated an effort in looking for its endogenous ligand. In 2011 we and another group reported the identification of 7α, 25-dihydroxyxcholesterol (7α, 25-OHC), an oxysterol, as the likely physiological ligand of EBI2. A few subsequently published studies further elucidated how 7α, 25-OHC bound to EBI2, and how a gradient of 7α, 25-OHC could be generated in vivo and regulated migration, activation, and functions of B cells, T cells, dendritic cells (DCs), monocytes/macrophages, and astrocytes. The identification of 7α, 25-OHC as a G protein-coupled receptor ligand revealed a previously unknown signaling system of oxysterols, a class of molecules which exert profound biological functions. Dysregulation of the synthesis or functions of these molecules is believed to contribute to inflammation and autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, cancer as well as metabolic diseases such as diabetes, obesity, and dyslipidemia. Therefore EBI2 may represent a promising target for therapeutic interventions for human diseases.
    Full-text · Article · Mar 2015
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