Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • It has only recently been appreciated

    2020-05-21

    It has only recently been appreciated that antigen-activated proton pump inhibitors list undertake two additional transient migrations during the early stages of T-dependent antibody responses. In the first of these, antigen-activated B cells migrate rapidly (within 2–3h) to the proton pump inhibitors list outer regions of the follicle before they relocate to the T–B boundary to receive T cell help (Figure 2) [9]. After interacting with T cells at the T–B boundary, activated B cells have also been shown to relocalize to interfollicular and outer follicular regions prior to their differentiation into early plasmablasts or entry into GCs (Figure 2) 10, 11, 12, 13. It transpires that both of these early B cell migratory steps are mediated by the chemoattractant receptor EBI2 (also known as GPR183) and its oxysterol ligand 9, 14, 15, 16, 17. In addition, modulation of chemotactic signal delivered to responding B cells through EBI2 plays a critical role in delivering them to the correct microenvironments to undergo plasmablast versus GC B cell differentiation. Thus, EBI2 is part of a network of chemoattractant receptors that regulates B cell localization, providing an extra dimension to the migratory cues provided by conventional chemokines and their receptors. Here, we review the role of EBI2 and oxysterols in controlling B cell migration and discuss how EBI2 collaborates with the chemokine receptors CXCR5, CCR7, and CXCR4 to position B cells appropriately during T-dependent antibody responses.
    EBI2 structure and expression The gene encoding EBI2 was originally identified together with EBI1 (CCR7) as the most highly upregulated gene in Epstein–Barr virus-infected Burkitt\'s lymphoma cells [18]. EBI2 belongs to the rhodopsin-like subfamily of seven transmembrane GPCRs [19]. Although it is not highly homologous to any other known GPCRs, sequence alignments have clustered EBI2 with lipid receptors and indicated highest sequence similarity with GPR18 19, 20. Studies of the activity of EBI2 have shown that it signals through the pertussis-sensitive Gαi protein [19]. Expression of EBI2 is most abundant in lymphoid tissues, with B cells, T cells, and various myeloid cells displaying high levels of EBI2 mRNA 15, 18, 19. EBI2 is expressed constitutively by mature B cells [17] and displays a characteristic expression pattern linked to B cell differentiation in both humans and mice. The already high constitutive EBI2 expression of naïve B cells is transiently increased after activation 9, 14, 17, 21, 22. By contrast, GC B cell differentiation is associated with the shutdown of EBI2 expression 14, 17, 21, 22. Plasma cells maintain expression of EBI2, albeit at lower levels than do naïve B cells 14, 17. Little is known about the transcriptional and molecular regulation of EBI2 expression. In vitro, cytokines such as interleukin (IL)-4, IL-6, and IL-10 have been shown to modulate EBI2 expression, whereas lipopolysaccharide (LPS) stimulation upregulates EBI2 transcription in most leukocyte populations 16, 22, 23. Similar to chemokine receptors, cell surface EBI2 expression is downregulated by ligand binding through β-arrestin-mediated receptor internalization 15, 16, 24.
    Oxysterols: the endogenous ligands for EBI2 Although EBI2 was initially suggested to have constitutive activity [19], it was subsequently deorphanized through the screening of tissue extracts with classic analytical methods and was shown to be the first GPCR activated by oxysterols 15, 16. The oxysterol 7α,25-dihydroxycholesterol (7α,25-OHC) was found to be a potent and selective agonist of EBI2 and its most likely endogenous ligand 15, 16. 7α,25-OHC is an oxygenated derivative of cholesterol and was previously identified as an intermediate product in the synthesis of bile acids [25]. Conversion of cholesterol into 7α,25-OHC is carried out by the biosynthetic enzymes cholesterol 25-hydroxylase (CH25H) and oxysterol 7α-hydroxylase (CYP7B1) [25], which are highly expressed by lymphoid stromal cells 15, 24. Although 7α,25-OHC appears as the major endogenous ligand for EBI2, inactivation of 7α,25-OHC synthesis via deletion of the Ch25h gene does not completely remove EBI2-ligand activity [24]. Thus natural oxysterols other than 7α,25-OHC may trigger EBI2 in vivo, consistent with the capacity of the receptor to bind and respond to several cholesterol derivates with high structural homology to 7α,25-OHC 15, 16.