EBI2 Is Highly Expressed in Multiple Sclerosis Lesions and Promotes Early CNS Migration of Encephalitogenic CD4 T Cells

Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Florian Wanke, Sonja Moos, Andrew L. Croxford, André P. Heinen, Stephanie Gräf, Bettina Kalt, Denise Tischner, Juan Zhang, Isabelle Christen, Julia Bruttger, Nir Yogev, Yilang Tang, Morad Zayoud, Nicole Israel, Khalad Karram, Sonja Reißig, Sonja M. Lacher, Christian Reichhold, Ilgiz A. Mufazalov, Avraham Ben-Nun, Tanja Kuhlmann, Nina Wettschureck, Andreas W. Sailer, Klaus Rajewsky, Stefano Casola, Ari Waisman, Florian C. Kurschus
Arrival of encephalitogenic T cells at inflammatory foci represents a critical step in development of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. EBI2 and its ligand, 7α,25-OHC, direct immune cell localization in secondary lymphoid organs. CH25H and CYP7B1 hydroxylate cholesterol to 7α,25-OHC. During EAE, we found increased expression of CH25H by microglia and CYP7B1 by CNS-infiltrating immune cells elevating the ligand concentration in the CNS. Two critical pro-inflammatory cytokines, interleukin-23 (IL-23) and interleukin-1 beta (IL-1β), maintained expression of EBI2 in differentiating Th17 cells. In line with this, EBI2 enhanced early migration of encephalitogenic T cells into the CNS in a transfer EAE model. Nonetheless, EBI2 was dispensable in active EAE. Human Th17 cells do also express EBI2, and EBI2 expressing cells are abundant within multiple sclerosis (MS) white matter lesions. These findings implicate EBI2 as a mediator of CNS autoimmunity and describe mechanistically its contribution to the migration of autoreactive T cells into inflamed organs.

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Wanke et al. show that EBI2 is expressed by Th17 cells in inflammation and that EBI2 promotes early CNS infiltration in passive EAE. Furthermore, they show that CH25H, CYP7B1, and 7α,25-OHC are upregulated in the CNS in EAE and that EBI2 expressing cells are highly present in MS lesions.


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