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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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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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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