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Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis

Nature Medicine volume 15, pages 626–632 (2009)Cite this article

Abstract

We describe here the paradoxical development of spontaneous experimental autoimmune encephalomyelitis (EAE) in transgenic mice expressing a myelin oligodendrocyte glycoprotein (MOG)-specific T cell antigen receptor (TCR) in the absence of MOG. We report that in Mog-deficient mice (Mog−/−), the autoimmune response by transgenic T cells is redirected to a neuronal cytoskeletal self antigen, neurofilament-M (NF-M). Although components of radically different protein classes, the cross-reacting major histocompatibility complex I-Ab–restricted epitope sequences of MOG35–55 and NF-M18–30 share essential TCR contact positions. This pattern of cross-reaction is not specific to the transgenic TCR but is also commonly seen in MOG35–55–I-Ab–reactive T cells. We propose that in the C57BL/6 mouse, MOG and NF-M response components add up to overcome the general resistance of this strain to experimental induction of autoimmunity. Similar cumulative responses against more than one autoantigen may have a role in spontaneously developing human autoimmune diseases.

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Figure 1: Paradoxical development of spontaneous EAE in MOG-specific 2D2 TCR–transgenic mice in two different Mog-deficient strains.
Figure 2: MOG-specific T cells respond to myelin from Mog−/− mice.
Figure 3: Fractionation of CNS proteins from Mog−/−, WT and Nefm−/− mice.
Figure 4: Identification of a protein that cross-reacts with MOG-specific 2D2–transgenic T cells.
Figure 5: NF-M reacts specifically with 2D2-transgenic T cells.
Figure 6: In vitro and in vivo cross-reactivity between NF-M– and MOG-specific T cells.

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Acknowledgements

MogCre/Cre, Nefm−/−, 2D2 and Mog−/− mice were generously provided by A. Waisman (Johannes Gutenberg University of Mainz), J.-P. Julien (Laval University), V.K. Kuchroo (Harvard Medical School) and D. Pham-Dinh (INSERM UMR 546). We thank F. Lottspeich for granting us permission to use his mass spectrometer. We thank L. Penner and I. Arnold-Ammer for technical support. This project was supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereiche (SFB) 571, Projects A1 and B6) and the Max Planck Society. H.S.D. is supported by a PhD fellowship (Portuguese Fundação para a Ciência ea Tecnologia (FCT) program SFRH/BD/15885/2005). Part of the study (conducted by H.W., R.L. and H.L.) was funded by the EU Project Neuropromise (PL 018637), and A.B.-N. was supported by the Israel Science Foundation and the National Multiple Sclerosis Society of New York (RG3195B8/2). A.B.-N. is an Alexander von Humboldt Prize Awardee.

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Author notes

  1. Florian C Kurschus

    Present address: Present address: I. Medizinische Klinik und Poliklinik, Johannes Gutenberg Universität, Mainz, Germany.,

  2. Klaus Dornmair, Florian C Kurschus and Roland S Liblau: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried, Germany

    Gurumoorthy Krishnamoorthy, Helena S Domingues, Klaus Dornmair, Florian C Kurschus & Hartmut Wekerle

  2. Institut National de la Santé et de la Recherche Médicale, Unité 563, Université Toulouse III, Paul-Sabatier, Toulouse, France

    Amit Saxena, Lennart T Mars & Roland S Liblau

  3. PhD Program in Experimental Biology and Biomedicine, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Helena S Domingues

  4. Institute of Clinical Neuroimmunology, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany

    Reinhard Mentele & Klaus Dornmair

  5. Department for Protein Analytics, Max Planck Institute of Biochemistry, Martinsried, Germany

    Reinhard Mentele

  6. Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel

    Avraham Ben-Nun

  7. Center for Brain Research, Medical University of Vienna, Vienna, Austria

    Hans Lassmann

Authors
  1. Gurumoorthy Krishnamoorthy
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Contributions

G.K. performed most of the experiments. G.K. and H.W. designed the study and wrote the manuscript with input from co-authors. A.S., L.T.M. and R.S.L. contributed EAE and T cell data. K.D. supervised protein purification and mass spectrometry and performed in silico searches. R.M. performed mass spectrometry. H.S.D. assisted in EAE experiments. A.B.-N. performed T cell line transfer EAE experiments. H.L. performed and interpreted histology. F.C.K. designed experiments and performed protein purification.

Corresponding author

Correspondence to Hartmut Wekerle.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–13, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 1029 kb)

Supplementary Video 1

Healthy 2D2 mouse. (MOV 2391 kb)

Supplementary Video 2

2D2 mouse with hind limb clasping phenotype. (MOV 2152 kb)

Supplementary Video 3

2D2 mouse with hind limb hyperextension (spasticity). (MOV 3284 kb)

Supplementary Video 4

Healthy 2D2 × Mog−/− mouse. (MOV 4442 kb)

Supplementary Video 5

2D2 × Mog−/− mouse with hind limb clasping. (MOV 3968 kb)

Supplementary Video 6

2D2 × Mog−/− mouse with hind limb clasping and hyperextension (spasticity). (MOV 3087 kb)

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Krishnamoorthy, G., Saxena, A., Mars, L. et al. Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis. Nat Med 15, 626–632 (2009). https://doi.org/10.1038/nm.1975

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