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  • Our data furthermore suggest that Ch h


    Our data furthermore suggest that Ch25h-induced oxysterols could play an important role in modulating the immune cell migration. Mechanistically, we observed impaired trafficking of CD44+CD4+ T cells in mice deficient for Ch25h. CD44+CD4+ T cells lacking EBI2, the receptor of 7α-25OHC, were delayed in reaching the CNS during EAE. CD44 molecule is a marker of memory T cells in mice and is expressed on antigen-activated T cells. CD44 is further involved in the homing of primed lymphocytes to the CNS [32]. Recruitment of encephalitogenic CD4+CD44+ T cells into the CNS is crucial for EAE development. A meta-analysis of EBI2 expression by real-time PCR on human peripheral blood cells suggested that EBI2 is expressed on CD4+ T lymphocytes at higher level in memory CD45RA− CD4+ T cells (the equivalent of CD44+CD4+ in mouse) compared to naïve T cells [16]. We confirmed that EBI2 expression is higher on human memory CD4+ T cells compared to naïve CD4+ T cells at the protein level. This suggests an important role for EBI2 on CD4+ T cells migration not only in murine but also in human T lymphocytes. IL-17A producing T cells participate in the induction of EAE [33][34]. IL-17A expression reaches its highest CNS level at disease initiation while it decreases at the peak of disease. On the other hand IFNγ achieves its highest value at the peak of disease [35]. Lymphocytes that produce IL-17A in the ae3 australia are expressing the activation marker CD44+. Those data suggest that activated CD44+ T cells that produce IL-17A reach the CNS at an early stage of the disease. In our model, we observed a delayed EAE onset in Ch25h−/− mice, which correlates with an accumulation of IL-17A producing CD4+ T cells within the dLN at the early stage of EAE disease. Those results are in accordance with recent studies showing that TH1 and TH17 cells harbor distinct migratory properties that drive their recruitment into the CNS [36]. We propose that different chemotactic responses to oxysterols could be considered as a new molecular mechanism distinguishing CD4+ T cells subset in regards to their migratory properties. Finally, we show that MoDCs are a rich source of Ch25h during EAE, corroborating previous notions of Ch25h expression in monocytes and macrophages [12]. MoDCs are detected under inflammatory states and reach the dLN during EAE [19]. As MoDCs can drive TH17 cells differentiation in situ by secretion of IL-1β, we assessed the expression of IL-1β and IL-23 from MoDCs of both wild-type and Ch25h−/− but we did not observe any differences in both cytokines expression. This suggests that oxysterols produced by MoDCs impact TH17 cell migration rather than their differentiation. MoDCs did not express Cyp7b1, the enzyme converting 25-OHC into the high-affinity ligand for EBI2, 7-α25-OHC. Moreover, we observed that cDCs, which are constitutively detected in the LN [19], express Cyp7b1. Thus, we propose that cDCs are responsible for the conversion of 25-OHC into 7α,25-OHC. This is in line with other reports which showed that Ch25h and Cyp7b1 enzymes were not expressed by the same cells during immune response [13].
    Conclusion We here describe for the first time a role for oxidized cholesterol metabolites, oxysterols, in promoting autoimmunity. Our data show that Ch25h-induced oxysterols drive a pro-inflammatory response during EAE by promoting encephalitogenic CD4+ T cells trafficking to the CNS. Impaired activated lymphocytes trafficking in the absence the oxysterol receptor EBI2 further results in delayed inflammatory cells recruitment into the CNS during EAE. The discovery of oxysterols as new mediators of different subsets of CD4+ T cell trafficking during EAE may lead to new targets to harness encephalitogenic immune cells not only during multiple sclerosis but also in other autoimmune diseases.
    Acknowledgments The authors thank C. Gameiro and JP. Aubry for cell sorting, Prof. S. Izui, Dr L. Guery, Dr I. Preuss and Dr P. Lalive for scientific input and technical assistance. Lipids profiles were measured at the Mouse Metabolic Facility (MEF) in the center for Integrative Genomics (CIG) at the University of Lausanne. This work was supported by the Swiss National Science Foundation (# 310030_138430), FP7-PEOPLE-CIG (# 293615), the Novartis Foundation for Medical-Biological Research (# 11A23) and the Swiss Multiple Sclerosis Society. F.C. is supported by the European Molecular Biology Organization (EMBO) and A.C. by the Hirsch Foundation. D.M. holds stipendiary professorships of the Swiss National Science Foundation (# PP00P3_152928) and is supported by the Klaus-Tschira Foundation and Gebert Rüf Stiftung. AW. S. is an employee of Novartis Pharma AG and holds stock and stock option in his company. The authors have no additional financial interests.