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

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.

References

  1. 1

    Sospedra, M. & Martin, R. Immunology of multiple sclerosis. Annu. Rev. Immunol. 23, 683–747 (2005).

    CAS  Article  Google Scholar 

  2. 2

    Hafler, D.A. et al. Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 357, 851–862 (2007).

    CAS  Article  Google Scholar 

  3. 3

    Olerup, O. & Hillert, J. HLA class II–associated genetic susceptibility in multiple sclerosis: a critical evaluation. Tissue Antigens 38, 1–15 (1991).

    CAS  Article  Google Scholar 

  4. 4

    van Oosten, B.W. et al. Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial. Neurology 49, 351–357 (1997).

    CAS  Article  Google Scholar 

  5. 5

    Segal, B.M. et al. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 7, 796–804 (2008).

    CAS  Article  Google Scholar 

  6. 6

    Coles, A.J. et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann. Neurol. 46, 296–304 (1999).

    CAS  Article  Google Scholar 

  7. 7

    Polman, C.H. et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899–910 (2006).

    CAS  Article  Google Scholar 

  8. 8

    Lassmann, H. & Ransohoff, R.M. The CD4-TH1 model for multiple sclerosis: a critical [correction of crucial] re-appraisal. Trends Immunol. 25, 132–137 (2004).

    CAS  Article  Google Scholar 

  9. 9

    Goverman, J., Perchellet, A. & Huseby, E.S. The role of CD8+ T cells in multiple sclerosis and its animal models. Curr. Drug Targets Inflamm. Allergy 4, 239–245 (2005).

    CAS  Article  Google Scholar 

  10. 10

    Friese, M.A. & Fugger, L. Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy? Brain 128, 1747–1763 (2005).

    Article  Google Scholar 

  11. 11

    Hauser, S.L. et al. Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions. Ann. Neurol. 19, 578–587 (1986).

    CAS  Article  Google Scholar 

  12. 12

    Booss, J., Esiri, M.M., Tourtellotte, W.W. & Mason, D.Y. Immunohistological analysis of T lymphocyte subsets in the central nervous system in chronic progressive multiple sclerosis. J. Neurol. Sci. 62, 219–232 (1983).

    CAS  Article  Google Scholar 

  13. 13

    Babbe, H. et al. Clonal expansions of CD8+ T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J. Exp. Med. 192, 393–404 (2000).

    CAS  Article  Google Scholar 

  14. 14

    Junker, A. et al. Multiple sclerosis: T cell receptor expression in distinct brain regions. Brain 130, 2789–2799 (2007).

    Article  Google Scholar 

  15. 15

    Huseby, E.S. et al. A pathogenic role for myelin-specific CD8+ T cells in a model for multiple sclerosis. J. Exp. Med. 194, 669–676 (2001).

    CAS  Article  Google Scholar 

  16. 16

    Sun, D. et al. Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J. Immunol. 166, 7579–7587 (2001).

    CAS  Article  Google Scholar 

  17. 17

    Koh, D.R. et al. Less mortality but more relapses in experimental allergic encephalomyelitis in CD8−/− mice. Science 256, 1210–1213 (1992).

    CAS  Article  Google Scholar 

  18. 18

    Jiang, H., Zhang, S.I. & Pernis, B. Role of CD8+ T cells in murine experimental allergic encephalomyelitis. Science 256, 1213–1215 (1992).

    CAS  Article  Google Scholar 

  19. 19

    Najafian, N. et al. Regulatory functions of CD8+CD28 T cells in an autoimmune disease model. J. Clin. Invest. 112, 1037–1048 (2003).

    CAS  Article  Google Scholar 

  20. 20

    Sawcer, S. et al. A high-density screen for linkage in multiple sclerosis. Am. J. Hum. Genet. 77, 454–467 (2005).

    Article  Google Scholar 

  21. 21

    Haines, J.L. et al. Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group. Hum. Mol. Genet. 7, 1229–1234 (1998).

    CAS  Article  Google Scholar 

  22. 22

    Jersild, C. et al. Histocompatibility determinants in multiple sclerosis, with special reference to clinical course. Lancet 2, 1221–1225 (1973).

    CAS  Article  Google Scholar 

  23. 23

    Marrosu, M.G. et al. Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia. Hum. Mol. Genet. 10, 2907–2916 (2001).

    CAS  Article  Google Scholar 

  24. 24

    Rubio, J.P. et al. Genetic dissection of the human leukocyte antigen region by use of haplotypes of Tasmanians with multiple sclerosis. Am. J. Hum. Genet. 70, 1125–1137 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Burfoot, R.K. et al. SNP mapping and candidate gene sequencing in the class I region of the HLA complex: searching for multiple sclerosis susceptibility genes in Tasmanians. Tissue Antigens 71, 42–50 (2008).

    CAS  PubMed  Google Scholar 

  26. 26

    Fogdell-Hahn, A., Ligers, A., Gronning, M., Hillert, J. & Olerup, O. Multiple sclerosis: a modifying influence of HLA class I genes in an HLA class II associated autoimmune disease. Tissue Antigens 55, 140–148 (2000).

    CAS  Article  Google Scholar 

  27. 27

    Harbo, H.F. et al. Genes in the HLA class I region may contribute to the HLA class II-associated genetic susceptibility to multiple sclerosis. Tissue Antigens 63, 237–247 (2004).

    CAS  Article  Google Scholar 

  28. 28

    Brynedal, B. et al. HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PLoS ONE 2, e664 (2007).

    Article  Google Scholar 

  29. 29

    Lincoln, M.R. et al. A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis. Nat. Genet. 37, 1108–1112 (2005).

    CAS  Article  Google Scholar 

  30. 30

    Chao, M.J. et al. Transmission of class I/II multi-locus MHC haplotypes and multiple sclerosis susceptibility: accounting for linkage disequilibrium. Hum. Mol. Genet. 16, 1951–1958 (2007).

    CAS  Article  Google Scholar 

  31. 31

    Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996).

    CAS  Article  Google Scholar 

  32. 32

    Koeleman, B.P., Dudbridge, F., Cordell, H.J. & Todd, J.A. Adaptation of the extended transmission/disequilibrium test to distinguish disease associations of multiple loci: the Conditional Extended Transmission/Disequilibrium Test. Ann. Hum. Genet. 64, 207–213 (2000).

    CAS  Article  Google Scholar 

  33. 33

    Gregersen, J.W. et al. Functional epistasis on a common MHC haplotype associated with multiple sclerosis. Nature 443, 574–577 (2006).

    CAS  Article  Google Scholar 

  34. 34

    Honma, K. et al. Identification of an epitope derived from human proteolipid protein that can induce autoreactive CD8+ cytotoxic T lymphocytes restricted by HLA-A3: evidence for cross-reactivity with an environmental microorganism. J. Neuroimmunol. 73, 7–14 (1997).

    CAS  Article  Google Scholar 

  35. 35

    Klein, L., Klugmann, M., Nave, K.A., Tuohy, V.K. & Kyewski, B. Shaping of the autoreactive T cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nat. Med. 6, 56–61 (2000).

    CAS  Article  Google Scholar 

  36. 36

    Serafini, B. et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J. Exp. Med. 204, 2899–2912 (2007).

    CAS  Article  Google Scholar 

  37. 37

    Alam, S.M. & Gascoigne, N.R. Posttranslational regulation of TCR Vα allelic exclusion during T cell differentiation. J. Immunol. 160, 3883–3890 (1998).

    CAS  PubMed  Google Scholar 

  38. 38

    McGargill, M.A., Derbinski, J.M. & Hogquist, K.A. Receptor editing in developing T cells. Nat. Immunol. 1, 336–341 (2000).

    CAS  Article  Google Scholar 

  39. 39

    Sim, B.C. et al. Thymic skewing of the CD4/CD8 ratio maps with the T cell receptor α-chain locus. Curr. Biol. 8, 701–704 (1998).

    CAS  Article  Google Scholar 

  40. 40

    Wallstrom, E. et al. Increased reactivity to myelin oligodendrocyte glycoprotein peptides and epitope mapping in HLA DR2(15)+ multiple sclerosis. Eur. J. Immunol. 28, 3329–3335 (1998).

    CAS  Article  Google Scholar 

  41. 41

    Vandenbark, A.A. et al. Recombinant TCR ligand induces tolerance to myelin oligodendrocyte glycoprotein 35–55 peptide and reverses clinical and histological signs of chronic experimental autoimmune encephalomyelitis in HLA-DR2 transgenic mice. J. Immunol. 171, 127–133 (2003).

    CAS  Article  Google Scholar 

  42. 42

    McMahon, E.J., Bailey, S.L., Castenada, C.V., Waldner, H. & Miller, S.D. Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nat. Med. 11, 335–339 (2005).

    CAS  Article  Google Scholar 

  43. 43

    Janssen, E.M. et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856 (2003).

    CAS  Article  Google Scholar 

  44. 44

    Shedlock, D.J. & Shen, H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300, 337–339 (2003).

    CAS  Article  Google Scholar 

  45. 45

    Sun, J.C. & Bevan, M.J. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300, 339–342 (2003).

    CAS  Article  Google Scholar 

  46. 46

    Hogquist, K.A., Baldwin, T.A. & Jameson, S.C. Central tolerance: learning self-control in the thymus. Nat. Rev. Immunol. 5, 772–782 (2005).

    CAS  Article  Google Scholar 

  47. 47

    Liston, A., Lesage, S., Wilson, J., Peltonen, L. & Goodnow, C.C. Aire regulates negative selection of organ-specific T cells. Nat. Immunol. 4, 350–354 (2003).

    CAS  Article  Google Scholar 

  48. 48

    Pascolo, S. et al. HLA-A2.1-restricted education and cytolytic activity of CD8+ T lymphocytes from β2 microglobulin (β2m) HLA-A2.1 monochain transgenic H-2Db β2m double knockout mice. J. Exp. Med. 185, 2043–2051 (1997).

    CAS  Article  Google Scholar 

  49. 49

    Vitiello, A., Marchesini, D., Furze, J., Sherman, L.A. & Chesnut, R.W. Analysis of the HLA-restricted influenza-specific cytotoxic T lymphocyte response in transgenic mice carrying a chimeric human-mouse class I major histocompatibility complex. J. Exp. Med. 173, 1007–1015 (1991).

    CAS  Article  Google Scholar 

  50. 50

    Madsen, L. et al. Mice lacking all conventional MHC class II genes. Proc. Natl. Acad. Sci. USA 96, 10338–10343 (1999).

    CAS  Article  Google Scholar 

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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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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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Supplementary Figs. 1–7 and Supplementary Methods (PDF 4514 kb)

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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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