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CD8+ T cells maintain tolerance to myelin basic protein by 'epitope theft'

Nature Immunology volume 5, pages 606–614 (2004)Cite this article

Abstract

Myelin basic protein–specific CD8+ T cells can induce central nervous system autoimmunity; however, immune tolerance prevents these autoreactive cells from causing disease. To define the mechanisms that mediate tolerance, we developed two T cell receptor–transgenic mouse lines with different affinities for the H-2Kk-restricted myelin basic protein epitope consisting of amino acids 79–87 (MBP(79–87)). We observed both thymic deletion and peripheral tolerance in the lower-affinity T cells. The higher-affinity T cells, however, showed no evidence of tolerance induction and were able to prevent tolerance of the lower-affinity T cells by removing H-2Kk–MBP(79–87) complexes from antigen-presenting cells without proliferating. This form of immune regulation could limit responses of self-reactive T cells that escape other tolerance mechanisms.

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Figure 1: Central tolerance in 8.6 TCR-transgenic mice.
Figure 2: Peripheral tolerance in 8.6 TCR-transgenic mice.
Figure 3: The 8.8 T cells are not deleted in the thymus or periphery.
Figure 4: The 8.8 T cells are hyporesponsive to MBP in vivo despite showing higher affinity for H-2Kk–MBP(79–87) in vitro than do 8.6 T cells.
Figure 5: The 8.8 T cells rescue 8.6 T cells from tolerance in mixed BMC.
Figure 6: Inhibitory activity of 8.8 T cells is epitope specific.
Figure 7: The 8.8 T cells inhibit proliferation of 8.6 T cells by acting on DCs.

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Acknowledgements

We thank N. Mausolf and M. Ottele for animal husbandry and technical support; A. Seamons for assistance with DC purifications; and E. Huseby for generation of cytotoxic T lymphocyte lines. We also thank T. Brabb, S. Cabbage, E. Huseby and A. Seamons for critical reading of the manuscript and discussions. Supported by National Institutes of Health (NS35126 and NS43417 to J.G.) and Public Health Service (T32 GM07270 to A.P.).

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Authors and Affiliations

  1. Department of Immunology, University of Washington, Box 357650, Seattle, 98195, Washington, USA

    Antoine Perchellet, Ingunn Stromnes & Joan Goverman

  2. Molecular and Cellular Biology Graduate Program, University of Washington, Box 357650, Seattle, 98195, Washington, USA

    Jennifer M Pang

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  1. Antoine Perchellet
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Correspondence to Joan Goverman.

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Perchellet, A., Stromnes, I., Pang, J. et al. CD8+ T cells maintain tolerance to myelin basic protein by 'epitope theft'. Nat Immunol 5, 606–614 (2004). https://doi.org/10.1038/ni1073

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