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Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis

Nature Medicine volume 11, pages 328–334 (2005)Cite this article

Abstract

Immunization with myelin antigens leads to the development of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. The disease can also be induced by the transfer of encephalitogenic CD4+ T helper (TH) lymphocytes into naive mice. These T cells need to re-encounter their cognate antigen in the context of major histocompatibility complex (MHC) class II–bearing antigen-presenting cells (APCs) in order to recognize their target. The cell type and location of the APC mediating T-cell entry into the central nervous system (CNS) remain unknown. Here, we show that APCs of the lymphoreticular system and of the CNS parenchyma are dispensable for the immune invasion of the CNS. We also describe that a discrete population of vessel-associated dendritic cells (DCs) is present in human brain tissue. In mice, CD11c+ DCs alone are sufficient to present antigen in vivo to primed myelin-reactive T cells in order to mediate CNS inflammation and clinical disease development.

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Figure 1: Secondary lymphoid tissues are not a pivotal homing site for encephalitogenic lymphocytes.
Figure 2: MHC class II molecules in the CNS parenchyma are not crucial for the development of EAE.
Figure 3: Localization of MHC class II–expressing cells in CD11c–H2-Ab1/H2-Ab1−/− mice.
Figure 4: DC-restricted MHC class II expression is sufficient to permit disease development.
Figure 5: Presence of vessel-associated CD209+ cells in multiple sclerosis lesions.
Figure 6: Augmenting the number of DCs increases EAE severity.

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Acknowledgements

This work was supported by a grant from the National Center for Competence in Research (NCCR) Neural Plasticity and Repair (to B.B.), the National Science Foundation of Switzerland (to B.B.), an unrestricted grant by Serono Pharmaceuticals Geneva (to B.B.) and the US National Institutes of Health (to R.J.N., AI49580). B.B. is a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society. M.G. holds a fellowship of the Roche Research Foundation of Switzerland. F.L.H. is supported by the Stammbach foundation. The authors thank P. Bargsten, C. Skulina (University of Zurich) and B. Durell (Dartmouth Medical School) for technical support. The authors further thank M. Kurrer for discussions and A. Fontana (University of Zurich) for discussions and critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Neurology, Neuroimmunology Unit, University Hospital Zurich, Frauenklinkstrasse 10, CH-8091, Switzerland

    Melanie Greter, Norbert Goebels & Burkhard Becher

  2. Department of Pathology, Institute of Neuropathology, University Hospital Zurich, Schmelzbergstrasse 12, CH-8091, Switzerland

    Frank L Heppner

  3. Division of Rheumatology, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Maria P Lemos & Terri Laufer

  4. Department of Pathology, Institute for Clinical Pathology, University Hospital Zurich, Haeldeliweg 4, CH-8091, Switzerland

    Bernhard M Odermatt

  5. Department of Microbiology and Immunology, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, 03755, New Hampshire, USA

    Randolph J Noelle

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Correspondence to Burkhard Becher.

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Supplementary information

Supplementary Fig. 1

Location of adoptively transferred encephalitogenic CD4+ T cells prior to CNS infiltration. (PDF 106 kb)

Supplementary Fig. 2

Location of BM-derived cells in the systemic immune compartment of BM-chimeras. (PDF 789 kb)

Supplementary Fig. 3

Treatment with FL drastically increases the number of CNS-associated DCs and augments disease severity. (PDF 76 kb)

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Greter, M., Heppner, F., Lemos, M. et al. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med 11, 328–334 (2005). https://doi.org/10.1038/nm1197

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