Influence of a dominant cryptic epitope on autoimmune T cell tolerance.
The rules governing which T cells are inactivated during peptide-induced tolerance are unclear. Here we show that MBP(89-101) contains three overlapping but distinct T cell epitopes that are restricted by a single major histocompatibility complex (MHC) class II molecule. The dominant epitope is not processed from MBP and is not relevant to the induction of autoimmunity. Pathogenic T cells recognize two minor epitopes that are processed from MBP but are presented only poorly after exposure to MBP(89-101). Induction of immunological tolerance by MBP(89-101) therefore inactivates T cells that recognize the dominant epitope and disease-relevant T cells escape tolerance. The topology of the three epitopes implicates asparagine endopeptidase as the enzyme that controls recognition of this region of MBP. Our results highlight the need to use peptides that mimic the binding of processed antigen fragments to MHC molecules for successful modulation of disease-relevant T cells.
Anderton
Stephen M
SM
University of Edinburgh, Institute of Cell, Animal and Population Biology, King's Buildings, West Mains Road, Edinburgh EH9 3JT, UK. steve.anderton@ed.ac.uk
Viner
Nicholas J
NJ
Matharu
Philip
P
Lowrey
Pauline A
PA
Wraith
David C
DC
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D015551:Autoimmunity; D002999:Clone Cells; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D000949:Histocompatibility Antigens Class II; D007108:Immune Tolerance; D016056:Immunodominant Epitopes / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C446766:myelin basic protein 89-101