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Myelin-Reactive Type B T Cells and T Cells Specific for Low-Affinity MHC-Binding Myelin Peptides Escape Tolerance in HLA-DR Transgenic Mice¹

Kazuyuki Kawamura^*, Katherine A. McLaughlin, Robert Weissert and Thomas G. Forsthuber^2,*

^* Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249; Harvard University and Dana-Farber Cancer Institute, Boston, MA 02115; and Hertie Institute for Clinical Brain Research, Department of General Neurology, University of Tübingen, Tübingen, Germany

Genes of the MHC show the strongest genetic association with multiple sclerosis (MS), but the underlying mechanisms have remained unresolved. In this study, we asked whether the MS-associated MHC class II molecules, HLA-DRB1*1501, HLA-DRB5*0101, and HLA-DRB1*0401, contribute to autoimmune CNS demyelination by promoting pathogenic T cell responses to human myelin basic protein (hMBP), using three transgenic (Tg) mouse lines expressing these MHC molecules. Unexpectedly, profound T cell tolerance to the high-affinity MHC-binding hMBP82-100 epitope was observed in all Tg mouse lines. T cell tolerance to hMBP82-100 was abolished upon back-crossing the HLA-DR Tg mice to MBP-deficient mice. In contrast, T cell tolerance was incomplete for low-affinity MHC-binding hMBP epitopes. Furthermore, hMBP82-100-specific type B T cells escaped tolerance in HLA-DRB5*0101 Tg mice. Importantly, T cells specific for low-affinity MHC-binding hMBP epitopes and hMBP82-100-specific type B T cells were highly encephalitogenic. Collectively, the results show that MS-associated MHC class II molecules are highly efficient at inducing T cell tolerance to high-affinity MHC-binding epitope, whereas autoreactive T cells specific for the low-affinity MHC-binding epitopes and type B T cells can escape the induction of T cell tolerance and may promote MS.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant NS-428846 from the National Institutes of Health, and Grants RG3499 and RG3701 from the National Multiple Sclerosis Society (to T.G.F.). K.K. is recipient of a Postdoctoral Fellowship from the National Multiple Sclerosis Society.

² Address correspondence and reprint requests to Dr. Thomas G. Forsthuber, Department of Biology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249. E-mail address: thomas.forsthuber{at}utsa.edu

³ Abbreviations used in this paper: MS, multiple sclerosis; MBP, myelin basic protein; EAE, experimental autoimmune encephalomyelitis; h, human; m, murine; Tg, transgenic; BCL, B cell line; LN, lymph node; TCL, T cell line; TCC, T cell clone; AEP, asparagine endopeptidase.