Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells

Abstract

Intrathymic expression of tissue-specific self antigens may be involved in immunological tolerance and protection from autoimmune disease. We have analyzed the role of T-cell tolerance to proteolipid protein (PLP), the main protein of the myelin sheath, in susceptibility to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Intrathymic expression of PLP was largely restricted to the shorter splice variant, DM20. Expression of DM20 by thymic epithelium was sufficient to confer T-cell tolerance to all epitopes of PLP in EAE-resistant C57BL/6 mice. In contrast, the major T-cell epitope in SJL/J mice was only encoded by the central nervous system-specific exon of PLP, but not by thymic DM20. Thus, lack of tolerance to this epitope offers an explanation for the exquisite susceptibility of SJL/J mice to EAE. As PLP expression in the human thymus is also restricted to the DM20 isoform, these findings have implications for selection of the autoimmune T-cell repertoire in multiple sclerosis.

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Figure 1: Tolerance to PLP by radio-resistant thymic epithelium and hemopoietic cells.
Figure 3: PLP-specific T-cell epitopes in BL/6 wild type, BL/6 PLP-deficient and SJL/J mice.
Figure 2: PLP expression in thymus of mouse and human.

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Acknowledgements

We thank B. Arnold and J. Trotter for suggestions on the manuscript; K. Hexel for support in cell sorting; and S. Hagl (Department of Cardiac Surgery, University of Heidelberg, Germany) for providing human thymic tissue. Support of this study by the German Cancer Research Center, the Deutsche Forschungsgemeinschaft (DFG Ky 7/-1 to B.K.), the International Agency for Research on Cancer (Research Training Fellowship to L.K.), and the National Institutes of Health (grants NS 36054 and NS 37476 to V.K.T.) is acknowledged.

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Correspondence to Bruno Kyewski.

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Klein, L., Klugmann, M., Nave, K. et al. 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). https://doi.org/10.1038/71540

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