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Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis

Nature Medicine volume 14, pages 1227–1235 (2008)Cite this article

Abstract

The major known genetic risk factors in multiple sclerosis reside in the major histocompatibility complex (MHC) region. Although there is strong evidence implicating MHC class II alleles and CD4+ T cells in multiple sclerosis pathogenesis, possible contributions from MHC class I genes and CD8+ T cells are controversial. We have generated humanized mice expressing the multiple sclerosis–associated MHC class I alleles HLA-A*0301 (encoding human leukocyte antigen-A3 (HLA-A3)) and HLA-A*0201 (encoding HLA-A2) and a myelin-specific autoreactive T cell receptor (TCR) derived from a CD8+ T cell clone from an individual with multiple sclerosis to study mechanisms of disease susceptibility. We demonstrate roles for HLA-A3–restricted CD8+ T cells in induction of multiple sclerosis–like disease and for CD4+ T cells in its progression, and we also define a possible mechanism for HLA-A*0201–mediated protection. To our knowledge, these data provide the first direct evidence incriminating MHC class I genes and CD8+ T cells in the pathogenesis of human multiple sclerosis and reveal a network of MHC interactions that shape the risk of multiple sclerosis.

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Figure 1: Expression and functional activity of 2D1-TCR+CD8+ T cells in transgenic mice.
Figure 2: Spontaneous and PLP45–53–induced multiple sclerosis–like disease in A3–2D1-TCR double-transgenic mice.
Figure 3: Infiltration of the CNS by CD8+ T cells and later by CD4+ T cells concomitantly with epitope spreading.
Figure 4: HLA-A*0201 protects from development of multiple sclerosis–like disease.
Figure 5: Addition of the HLA-A*0201 transgene in A3–2D1-TCR mice reduces 2D1-TCR+CD8+ T cell selection and transgenic TCR surface expression.
Figure 6: 2D1-TCR+ T cells that escape A2-mediated negative selection show reduced TCR surface expression.

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Acknowledgements

We thank H. von Boehmer (Dana-Farber Cancer Institute) for the BW58TCR-αβ− T cell hybridoma, A. McMichael (University of Oxford) for GAP.A3, W.E. Biddison (US National Institutes of Health) for providing DNA and RNA from the 2D1 T cell clone and N. Willcox and A. Vincent for critical reading of the manuscript. Work in the authors' laboratories is supported by the Danish (to L. Fugger) and UK (to L. Fugger and E.Y.J.) Medical Research Councils, the Karen Elise Jensen Foundation, the Lundbeck Foundation, the Danish Multiple Sclerosis Society, the European Union (European Commission Descartes Prize and FP6 Neuropromise, Mugen and ARDIS) and GB Holding (Viby) Aps (L. Fugger). M.A.F. was supported by the Deutsche Forschungsgemeinschaft (DFG FR1720/1-1) and a Medical Research Council UK Career Development Fellowship and is supported by the Deutsche Forschungsgemeinschaft Emmy Noether Programme (FR1720/3-1). R.E. is supported by the Schweizerische MS Gesellschaft and a Berrow Scholarship. E.Y.J. is a Cancer Research UK Principal Research Fellow.

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Authors and Affiliations

  1. Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, OX3 9DS, Oxford, UK

    Manuel A Friese, Karen B Jakobsen, Lone Friis, Ruth Etzensperger, Róisín M McMahon, Véronique Huygelen, John I Bell & Lars Fugger

  2. Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, OX3 9DS, Oxford, UK

    Manuel A Friese, Matthew J Craner & Lars Fugger

  3. Institut für Neuroimmunologie und Klinische MS-Forschung, Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany

    Manuel A Friese

  4. Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, OX3 7BN, Oxford, UK

    Róisín M McMahon & E Yvonne Jones

  5. Clinical Institute, Aarhus University Hospital, Skejby Sygehus, Brendstrupgaardsvej 100, 8200 N, Aarhus, Denmark

    Lise T Jensen & Lars Fugger

  6. Office of the Regius Professor of Medicine, The Richard Doll Building, Roosevelt Drive, University of Oxford, OX3 7BN, Oxford, UK

    John I Bell

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Contributions

M.A.F. and L. Fugger formulated the hypothesis and initiated and organized the study. M.A.F. constructed the transgenic vectors, generated the transgenic mice, performed the main experimental work and analyzed the data. K.B.J. and M.J.C. conducted the histological and immunohistochemical analyses. L.Friis, R.E., R.M.M., L.T.J. and V.H. helped with some experimental procedures. L. Fugger oversaw the experiments, analyzed the data and provided the funding for the research. M.A.F. drafted the manuscript, and E.Y.J, J.I.B. and L. Fugger helped with writing the final manuscript.

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Correspondence to Lars Fugger.

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Friese, M., Jakobsen, K., Friis, L. et al. Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis. Nat Med 14, 1227–1235 (2008). https://doi.org/10.1038/nm.1881

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