Myelin-reactive type B T cells and T cells specific for low-affinity MHC-binding myelin peptides escape tolerance in HLA-DR transgenic mice.

The Journal of Immunology : Official Journal of the American Association of Immunologists
Kazuyuki KawamuraThomas G Forsthuber

Abstract

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...Continue Reading

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Citations

Nov 12, 2009·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Joseph J SabatinoBrian D Evavold
Aug 19, 2015·Neurology. Neuroimmunology and Neuroinflammation·Niannian JiThomas G Forsthuber
Jan 29, 2019·Precision Clinical Medicine·Xiaoxiao Wan, Emil R Unanue
Sep 13, 2014·Future Virology·Matthew F CusickRobert S Fujinami
Sep 8, 2012·Nature Reviews. Immunology·James F Mohan, Emil R Unanue
Oct 15, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Niannian JiThomas G Forsthuber
Aug 14, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jacqueline A QuandtKouichi Ito

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