Cell Reports (Jan 2017)
EBI2 Is Highly Expressed in Multiple Sclerosis Lesions and Promotes Early CNS Migration of Encephalitogenic CD4 T Cells
- 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
Affiliations
- Florian Wanke
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Sonja Moos
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Andrew L. Croxford
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- André P. Heinen
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Stephanie Gräf
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Bettina Kalt
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Denise Tischner
- Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
- Juan Zhang
- Analytical Sciences and Imaging, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland
- Isabelle Christen
- Analytical Sciences and Imaging, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland
- Julia Bruttger
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Nir Yogev
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Yilang Tang
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Morad Zayoud
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Nicole Israel
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Khalad Karram
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Sonja Reißig
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Sonja M. Lacher
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Christian Reichhold
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Ilgiz A. Mufazalov
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Avraham Ben-Nun
- Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
- Tanja Kuhlmann
- Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany
- Nina Wettschureck
- Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
- Andreas W. Sailer
- Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland
- Klaus Rajewsky
- Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin-Buch, Germany
- Stefano Casola
- IFOM–The FIRC Institute of Molecular Oncology, 20139 Milan, Italy
- Ari Waisman
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Florian C. Kurschus
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- DOI
- https://doi.org/10.1016/j.celrep.2017.01.020
- Journal volume & issue
-
Vol. 18,
no. 5
pp. 1270 – 1284
Abstract
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.
Keywords