Because EBI is expressed on the major subsets of
Because EBI2 is expressed on the major subsets of immune cells, and small molecule antagonists for EBI2 were recently described (Benned-Jensen et al., 2013, Gessier et al., 2014), EBI2 constitutes a tempting drug target reminiscent of the sphingosine-1-phosphate receptor superagonist fingolimod/Gilenya that is currently in clinical use for treatment of MS patients.
Experimental Procedures Detailed descriptions about mass spectrometry, single cell RT-PCR, and immunohistochemistry are provided in the Supplemental Information.
Acknowledgments We thank Petra Adams, Alexei Nikolaev, Marina Snetkova, and Elena Zurkowski for excellent technical assistance and Sebastian Attig (TRON, Mainz) and Alexander Hobhberger (FZI, Mainz) for cell sorting. This work was supported by the Deutsche Forschungsgemeinschaft SFB/TR-128 TPA3 to N.W. and F.C.K., TPA7 to A.W., TPZ1 to T.K., and by SFB/TR-156 TP C01 to F.C.K. and A.W. S.C. was supported by the Italian Association for Cancer Research (AIRC). A.W.S., I.C., and J.Z. are employees of Novartis Pharma, Basel, Switzerland and some of them hold stock and/or stock options in their company.
Microenvironmental niches for naïve and activated B cells Secondary lymphoid organs, such as the spleen and lymph nodes, are structurally and functionally compartmentalized to provide a set of microenvironmental niches that support the survival of resting B cells, as well as the activation and differentiation of BKT140 participating in antibody responses. In secondary lymphoid organs, B and T cells segregate to form B cell follicles that surround a central T cell zone (Figure 1). In the spleen, B cell follicles are surrounded by the marginal zone, an area rich in macrophages that also harbors a population of resident marginal zone B cells. Dendritic cell (DC) populations are localized in T cell areas as well as in interfollicular areas and the splenic marginal zone bridging channels, which are breaks in the marginal sinus where the T cell zone abuts the red pulp. Central to the compartmentalization of lymphoid organs is the localized production of chemokines and other guiding cues by networks of stromal cells (Table 1). The chemokine CXC ligand (CXCL)13 is made by follicular stromal cells, which comprise the marginal reticular cells in the outer follicle and a central network of follicular dendritic cells (FDCs) . Naïve recirculating B cells respond primarily to this chemokine as a result of their high expression of chemokine CXC receptor (CXCR)5 and therefore migrate to B cell follicles . By contrast, the fibroblastic reticular cell network in T cell zones is characterized by expression of the chemokines CC ligand (CCL)19 and CCL21, which mediate the migration of chemokine CC receptor (CCR)7-expressing T cells to these areas . During antibody responses, B cell migration is orchestrated to facilitate: (i) access to antigen; (ii) interactions with helper T cells; and (iii) homing to the specialized microenvironments that promote rapid or long-term antibody production. Naïve B cells patrol secondary lymphoid organs for the presence of antigen by rapid, random movement within follicles. After antigen encounter, B cells move to the boundary between B cell follicles and T cell areas where they interact with T helper cells and undergo initial proliferation (Figure 2) . This movement occurs about 6h after activation and is directed by the antigen-mediated upregulation of CCR7; the receptor for the T cell zone chemokines CCL19 and CCL21 . Early in the response, proliferating B cells begin to follow one of two alternate fates by differentiating into short-lived plasma cells or germinal center (GC) B cells. B cells recruited into the former pathway migrate to extrafollicular sites (Figure 2) where their proliferation and differentiation into plasmablasts and plasma cells is sustained . Alternatively, B cells can localize to the FDC-dense areas in the center of follicles where they seed GCs (Figure 2) 7, 8. As the response progresses, B cells leave GC reactions either as long-lived plasma cells, which take up residency in the bone marrow, or as memory B cells .