Abstract
Interleukin 17–producing T helper cells (TH-17 cells) are important in experimental autoimmune encephalomyelitis, but their route of entry into the central nervous system (CNS) and their contribution relative to that of other effector T cells remain to be determined. Here we found that mice lacking CCR6, a chemokine receptor characteristic of TH-17 cells, developed TH-17 responses but were highly resistant to the induction of experimental autoimmune encephalomyelitis. Disease susceptibility was reconstituted by transfer of wild-type T cells that entered into the CNS before disease onset and triggered massive CCR6-independent recruitment of effector T cells across activated parenchymal vessels. The CCR6 ligand CCL20 was constitutively expressed in epithelial cells of choroid plexus in mice and humans. Our results identify distinct molecular requirements and ports of lymphocyte entry into uninflamed versus inflamed CNS and suggest that the CCR6-CCL20 axis in the choroid plexus controls immune surveillance of the CNS.
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Acknowledgements
We thank D. Jarrossay for cell sorting; T. Périnat and S. Minghelli for immunohistology analysis; E. Mira Catò and L. Perlini for technical assistance; B. Becher (University Hospital Zurich), C. Gerard (Harvard Medical School), J. Kirberg (Max-Plank Institute of Immunobiology) and M. Lipp (Max Delbruck Center) for mouse strains; L. Sallusto for discussions and support; and A. Almeida, A. Martín-Fontecha, G. Napolitani, U. Schenk and M. Uguccioni for discussions. Supported by the Swiss National Science Foundation (31-101962 to F.S.), the European Commission Sixth Framework Programme (LSB-CT-2005-518167 IINOCHEM and LSHG-CT-2005-005203 MUGEN), the US National Multiple Sclerosis Society (B.E. and C.C.), the Swiss Multiple Sclerosis Society, the Italian Foundation for Multiple Sclerosis (Stem Cell Project 2007-2009), the European Union-funded International Graduate Program in Molecular Medicine (A.R.), Boehringer Ingelheim Fonds (D.B.) and the Helmut Horten Foundation (to The Institute for Research in Biomedicine).
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A.R. did most of the experiments and contributed to experimental design; C.C., D. Baumjohann, F.B. and D. Bottinelli did experiments; S.L. generated the CCR6-knockout mice and provided intellectual input; B.E. and A.U. interpreted data, provided intellectual input and contributed to writing the manuscript; A.L. provided intellectual input and wrote the manuscript; and F.S. conceived the study, interpreted the data and wrote the manuscript.
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Reboldi, A., Coisne, C., Baumjohann, D. et al. C-C chemokine receptor 6–regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 10, 514–523 (2009). https://doi.org/10.1038/ni.1716
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DOI: https://doi.org/10.1038/ni.1716