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MHC class I–restricted myelin epitopes are cross-presented by Tip-DCs that promote determinant spreading to CD8+ T cells

Abstract

Myelin presentation to T cells in the central nervous system (CNS) sustains inflammation in multiple sclerosis (MS). CD4+ and CD8+ T cells contribute to MS, but only cells that present myelin to CD4+ T cells have been identified. We show that MHC class I–restricted myelin basic protein (MBP) was presented by oligodendrocytes and cross-presented by Tip–dendritic cells (DCs) during experimental autoimmune encephalomyelitis (EAE), an animal model of MS initiated by CD4+ T cells. Tip-DCs activated naive and effector CD8+ T cells ex vivo, and naive MBP-specific CD8+ T cells were activated in the CNS during CD4+ T cell–induced EAE. These results demonstrate that CD4+ T cell–mediated CNS autoimmunity leads to determinant spreading to myelin-specific CD8+ T cells that can directly recognize oligodendrocytes.

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Figure 1: Detection of MBP–H-2Kk by the 12H4 antibody and MBP-specific CD8+ T cells.
Figure 2: MBP–H-2Kk is presented predominantly by DCs in the CNS during CD4+ T cell–mediated EAE.
Figure 3: MBP–H-2Kk+ DCs in mice with EAE are phenotypically similar to tissue-infiltrating inflammatory monocytes.
Figure 4: MBP–H-2Kk+ DCs are CD11bhiCD103int nonclassical DCs.
Figure 5: MBP–H-2Kk+ CNS DCs in mice with CD4+ T cell–mediated EAE are Tip-DCs that facilitate determinant spreading to CD8+ T cells.
Figure 6: Oligodendrocytes present MBP–H-2Kk during CD4+ T cell–mediated EAE.
Figure 7: DCs from the CNS of naive mice present MBP–H-2Kk.

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Acknowledgements

We thank N. Mitiku, S. Lee, E. Pierson and S. Swarts for critical reading of the manuscript. This work was supported US National Institutes of Health grants (AI072737 and AI073748 to J.M.G.)

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Q.J. conducted most of the experiments and analyzed the data; L.C. assisted with some RT-PCR experiments and performed and analyzed in vivo experiments demonstrating activation of CD8+ T cells in the CNS and critiqued the manuscript; Q.J. and J.M.G. designed the study and wrote the manuscript, J.M.G. secured the funding.

Corresponding author

Correspondence to Joan M Goverman.

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The authors declare no competing financial interests.

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Ji, Q., Castelli, L. & Goverman, J. MHC class I–restricted myelin epitopes are cross-presented by Tip-DCs that promote determinant spreading to CD8+ T cells. Nat Immunol 14, 254–261 (2013). https://doi.org/10.1038/ni.2513

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