Nature Medicine
6, 56 - 61 (2000)
doi:10.1038/71540
Shaping of the autoreactive T-cell repertoire by a splice variant of
self protein expressed in thymic epithelial cellsLudger Klein1, 4, Matthias Klugmann2, 5, Klaus-Armin Nave2, V K Tuohy3
& Bruno Kyewski11
Tumor Immunology Programme, German Cancer Research
Center, INF 280, 69120 Heidelberg, Germany
2
Center for Molecular Biology, University of Heidelberg,
INF 282, 69120 Heidelberg, Germany
3
Department of Immunology, Lerner Research Institute,
The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
4
L.K. present address: Department of Cancer Immunology
and Aids, Dana Farber Cancer Institute, 44 Binney St., Boston, Massachusetts 02215, USA
5
M.K. present address: BASF Lynx, INF 515, 69120 Heidelberg, Germany
Correspondence should be addressed to Bruno Kyewski b.kyewski@dkfz-heidelberg.deIntrathymic 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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