As mentioned above EBI and

As mentioned above, EBI2 and its ligand show some similarities to the sphingosine 1-phosphate (S1P)/S1P-receptor system, which mediates T cell egress from lymph nodes. Blockade of this system yielded in the first oral drug for MS patients named fingolimod. Therefore, the hope that EBI2 deficiency would show an impact on EAE the common model in MS [16,35,36] was high. Although several research groups (personal communication) including us tested EBI2 deficient mice in the active EAE model, no effect on disease development in this model could be demonstrated [37]. Since we found that Th17 cell in the CNS of diseases animals expressed EBI2 to the highest extend, we thought to perform experiments in which encephalitogenic T Thonzonium Bromide were enriched for Th17 cells. Therefore, we expanded T cells from immunized mice with IL-23 and the cognate peptide and transferred these cells into RAG1 deficient animals. We found that the T cells, which lacked EBI2, transferred the disease with a delay of about 4 days compared to control T cells. Most importantly, the co-transfer of WT and EBI2 deficient encephalitogenic T cells demonstrated that WT cells more efficiently migrated into the CNS in early diseased animals than EBI2 deficient cells. This was highly supported by the finding that 2D2-TCR transgenic T cells specific for MOG, a myelin antigen [38], strongly accumulated in the blood before disease onset when compared to WT 2D2 cells. We also found a rise of the respective ligands in the CNS in mice with EAE. In line with this, expression of the responsible enzymes was strongly elevated in the spinal cord of mice before the onset of EAE. Importantly, we could demonstrate that CH25H, the rate-limiting enzyme in 7α,25-OHC generation, was strongly upregulated in microglia of EAE animals. Moreover, we also demonstrated that EBI2 is highly expressed by human Th17 cells and that many infiltrating cells in the inflamed white matter of MS patients are EBI2 positive. Interestingly, EBI2 expression is highly regulated as we could show with our EBI2 reporter mice. EBI2 was strongly upregulated or maintained by IL-23 and IL-1β but inhibited when T cells were activated in the presence of IL-2 or TGF-β and IL-6 [37] (Fig. 1). Similarly in the EAE model, Chalmin et al. previously demonstrated that EBI2 and CH25H might be responsible for the efficient egress of differentiated Th17 cells from the draining lymph nodes [31]. As discussed above, in active EAE we did not find differences in EAE development and only the transfer model could reveal a role of EBI2 expression on T cells for neuroinflammation [37]. Nevertheless, usage of full EBI2-KO mice may also preclude effects due to developmental adaptation processes with redundant mechanisms in place. Our data [37] as well as previous data of others [7,8] also revealed that the EBI2–7α,25-OHC system may rather have a subdominant role compared to chemokine receptors and their ligands in transmigration or localization in lymphoid tissues.