Abstract
Peripherally derived CD11b+ myeloid dendritic cells (mDCs), plasmacytoid DCs, CD8α+ DCs and macrophages accumulate in the central nervous system during relapsing experimental autoimmune encephalomyelitis (EAE). During acute relapsing EAE induced by a proteolipid protein peptide of amino acids 178–191, transgenic T cells (139TCR cells) specific for the relapse epitope consisting of proteolipid protein peptide amino acids 139–151 clustered with mDCs in the central nervous system, were activated and differentiated into T helper cells producing interleukin 17 (TH-17 cells). CNS mDCs presented endogenously acquired peptide, driving the proliferation of and production of interleukin 17 by naive 139TCR cells in vitro and in vivo. The mDCs uniquely biased TH-17 and not TH1 differentiation, correlating with their enhanced expression of transforming growth factor-β1 and interleukins 6 and 23. Plasmacytoid DCs and CD8α+ DCs were superior to macrophages but were much less efficient than mDCs in presenting endogenous peptide to induce TH-17 cells. Our findings indicate a critical function for CNS mDCs in driving relapses in relapsing EAE.
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Acknowledgements
We thank A. Dzionek (Miltenyi Biotec) for providing anti-PDCA-1; J. Marvin (Northwestern University) for cell sorting; M. Degutes for technical assistance; and colleagues at the Myelin Repair Foundation for discussions. Supported by the National Institutes of Health (NS-30871 and NS-26543; and AI-07476 to E.J.M.), the National Multiple Sclerosis Society (RG 3793-A-7; and FG 1563 A-1 to S.L.B.), the Myelin Repair Foundation, and Deutsche Forschungsgemeinschaft (B.S.).
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S.L.B. did most of the experiments; B.S. did the intracellular cytokine staining of 139TCR cells recovered from the CNS and helped with purification and phenotypic analysis of the CNS APC subsets; E.J.M. assisted with the immunohistochemistry; and S.D.M. provided intellectual input, secured the funding and guided the preparation of the manuscript.
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Supplementary information
Supplementary Fig. 1
Dendritic cells accumulate in the CNS of mice during relapsing EAE. (PDF 335 kb)
Supplementary Fig. 2
DC subsets and macrophages internalize myelin debris in the inflamed CNS. (PDF 271 kb)
Supplementary Fig. 3
MHC II and accessory molecule expression by DC subsets in the inflamed CNS. (PDF 239 kb)
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Bailey, S., Schreiner, B., McMahon, E. et al. CNS myeloid DCs presenting endogenous myelin peptides 'preferentially' polarize CD4+ TH-17 cells in relapsing EAE. Nat Immunol 8, 172–180 (2007). https://doi.org/10.1038/ni1430
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DOI: https://doi.org/10.1038/ni1430
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