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Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE

Abstract

Neurons have been neglected as cells with a major immune-regulatory function because they do not express major histocompatibility complex class II. Our data show that neurons are highly immune regulatory, having a crucial role in governing T-cell response and central nervous system (CNS) inflammation. Neurons induce the proliferation of activated CD4+ T cells through B7-CD28 and transforming growth factor (TGF)-β1–TGF-β receptor signaling pathways, resulting in amplification of T-cell receptor signaling through phosphorylated ZAP-70, interleukin (IL)-2 and IL-9. The interaction between neurons and T cells results in the conversion of encephalitogenic T cells to CD25+TGF-β1+CTLA-4+FoxP3+ T regulatory (Treg) cells that suppress encephalitogenic T cells and inhibit experimental autoimmune encephalomyelitis. Suppression is dependent on cytotoxic T lymphocyte antigen (CTLA)-4 but not TGF-β1. Autocrine action of TGF-β1, however, is important for the proliferative arrest of Treg cells. Blocking the B7 and TGF-β pathways prevents the CNS-specific generation of Treg cells. These findings show that generation of neuron-dependent Treg cells in the CNS is instrumental in regulating CNS inflammation.

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Figure 1: Neurons produce TGF-β1 and express B7 molecules.
Figure 2: T cells upregulate B7.1, B7.2, TGF-β1, TGF-βR and ICAM-1 on neurons, and neurons induce activation of effector T cells.
Figure 3: TGF-β1–TGF-βR and B7-CD28 signaling are essential for neuron-induced CD4+ T-cell proliferation and conversion to CD25+TGF-β1+ CTLA-4+ T cells.
Figure 4: Neuron-generated CD25+TGF-β1+CTLA-4+ T cells exert regulatory function through CTLA-4.
Figure 5: In vivo enrichment of CD4+TGF-β1+FoxP3+ T cells in the CNS of mice with EAE requires TGF-β and B7 signaling.
Figure 6: Neuron-induced and CNS-derived CD4+TGF-β1+ T cells suppress EAE.

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Acknowledgements

The authors would like to thank H. Wekerle and R. Holmdahl for their critical reading of the manuscript and for their suggestions and advice and T. Blom for graphical assistance. This work was supported by grants from The Swedish Foundation for Strategic Research, The Swedish Research Council – Natural Science, The Swedish Research Council – Medicine, Alfred Österlund Foundation, HM Gustav V's Foundation, The Royal Swedish Academy of Science, Royal Physiographic Society in Lund, M. Bergvalls Foundation, Åke Wiberg Foundation, Börje Dahlin Foundation, Segerfalk Foundation and The Crafoord Foundation.

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Correspondence to Shohreh Issazadeh-Navikas.

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Supplementary information

Supplementary Fig. 1

Neuron-induced Treg cells and role of TGF-β1. (PDF 788 kb)

Supplementary Fig. 2

CNS-infiltrating cells. (PDF 546 kb)

Supplementary Fig. 3

Fate of CD4+ encephalitogenic T cells upon cell-to-cell contact with neurons. (PDF 616 kb)

Supplementary Table 1

EAE parameters in mice coinjected with CD4+TGF-β1 or CD4+TGF-β1+ T cells upon adaptive transfer of MOG35-55 T cell line (PDF 68 kb)

Supplementary Methods (PDF 108 kb)

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Liu, Y., Teige, I., Birnir, B. et al. Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nat Med 12, 518–525 (2006). https://doi.org/10.1038/nm1402

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