The importance of EBI for B cell
The importance of EBI2 for B cell function was first suggested by the dramatic upregulation of this receptor in EBV-transformed Adrucil and further inferred from its regulation in activated and GC B cells (Birkenbach et al., 1993, Glynne et al., 2000, Shaffer et al., 2000). An involvement of EBI2 in pathology has also been suggested by its dysregulated expression in B cell-associated autoimmune and neoplastic diseases (Aalto et al., 2001, Ye et al., 2003). However, the function of EBI2 and the significance and implications of its modulation have long awaited clarification. This study provides evidence for a biological function of EBI2 and indicates that this receptor provides an extra dimension to B cell migration and differentiation. Modulation of EBI2 expression is necessary for ensuring both the rapid and long-term antibody production that are required for optimal protection against pathogens. Identification of the putative ligand for EBI2 and elucidation of the molecular mechanisms by which it controls B cell migration and differentiation may prove valuable in designing new vaccine strategies and potential therapeutics for immune disorders.
Acknowledgments We thank S. Tangye and A. Swarbrick for helpful discussions and critical reading of the manuscript; K. Wood, T. Camidge, and V. Turner for technical assistance; C. Brownlee for cell sorting; the staff of the Garvan Institute Biological Testing Facility for animal husbandry, and Ozgene for generation of mice. This work was funded by NHMRC Australia Program Grant 427620 to R.B, A.B., and C.R.M; D.G. and R.B. are supported by fellowships from the NHMRC Australia.
Introduction Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2, also known as GPR183) was discovered in 1993 in a screen of genes induced by in vitro Epstein-Barr virus (EBV) infection of a Burkitt’s lymphoma cell line (Birkenbach et al., 1993) and identified by sequence similarity as a G protein-coupled receptor (GPCR). EBI2 was shown to have an important role in B cell positioning in the germinal center reaction (Gatto et al., 2009, Pereira et al., 2009), resulting in fewer plasma cells and reduced antibody titers in EBI2-deficient animals. Also, CD4+ conventional dendritic cells (cDCs) are profoundly diminished in the spleen of EBI2 mutant mice (Gatto et al., 2013, Yi and Cyster, 2013). Recently, a role for EBI2 in differentiation of T follicular helper (Tfh) cells was demonstrated. Activated T cells were shown to migrate in an EBI2-dependent manner to the outer T zone to receive inducible T cell co-stimulator (ICOS) stimulation under IL-2 deprived conditions by IL-2 quenching DCs that fosters Tfh differentiation (Li et al., 2016). Furthermore, Suan et al. (2015) showed that Tfh cells in the germinal centers downregulate expression of EBI2. Thus, EBI2 regulates positioning of immune cells in secondary lymphoid organs. Oxysterols were recently identified as natural ligands for EBI2 (Hannedouche et al., 2011, Liu et al., 2011). The most active ligand, 7α,25-dihydroxycholesterol (7α,25-OHC), is generated via sequential hydroxylation of cholesterol by cholesterol-25-hydroxylase (CH25H) and 25-hydroxycholesterol by 7-alpha-hydroxylase (CYP7B1). In naive mice, CH25H is highly expressed in the spleen, whereas CYP7B1 is expressed quite ubiquitously with highest expression in the liver. In addition, both enzymes are expressed in lymphoid stromal cells (Hannedouche et al., 2011, Yi et al., 2012). Contradictory data were published about the role of CH25H in experimental autoimmune encephalomyelitis (EAE) (Chalmin et al., 2015, Reboldi et al., 2014), and no direct contribution of EBI2 in EAE pathogenesis has been described. Expression of EBI2 and its function for migration in vitro in T cells was recently reported (Chalmin et al., 2015, Hannedouche et al., 2011, Liu et al., 2011, Pereira et al., 2009). Pereira et al. (2009) used an EBI2 reporter mouse and found that most CD4+ T cells, but only approximately half of the CD8+ T cells, expressed EBI2. In vitro migration of murine T cell toward 7α,25-OHC was demonstrated previously (Chalmin et al., 2015, Liu et al., 2011).