title: Competition between two MHC binding registers in a single peptide processed from myelin basic protein influences tolerance and susceptibility to autoimmunity.
abstract: Experimental allergic encephalomyelitis (EAE) is an animal model for multiple sclerosis induced by stimulating myelin basic protein (MBP)-specific T cells. The MBP-specific repertoire in B10.PL mice is shaped by tolerance mechanisms that eliminate MBP121-150-specific T cells. In contrast, MBPAc1-11-specific T cells escape tolerance and constitute the encephalitogenic repertoire. To determine if this differential tolerance is caused by differences in the abundance of MBP epitopes generated by processing, MBP peptides were eluted from I-Au complexes and analyzed by mass spectrometry. Peptides were identified from both the NH2-terminal and MBP121-150 regions. Unexpectedly, MBPAc1-18 and Ac1-17, which contain the MBPAc1-11 epitope, were much more abundant than MBP121-150 peptides. The results demonstrate that competition between two I-Au binding registers, a low affinity register defined by MBPAc1-11 and a high affinity register defined by MBP5-16, prevents most of the NH2-terminal naturally processed peptides from binding in the MBPAc1-11 register. The small fraction of MBPAc1-18 bound in the MBPAc1-11 register is not sufficient to induce tolerance but provides a ligand for MBPAc1-11-specific T cells during disease. These results provide a basis for both the lack of tolerance to MBPAc1-11 and the ability of this epitope to become a target during autoimmunity.
authors.affiliation: Department of Immunology, Box 357650, University of Washington, Seattle, WA 98195, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Seamons
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sutton
authors.forename: Dina
authors.initials: D
authors.lastname: Bai
authors.forename: Emily
authors.initials: E
authors.lastname: Baird
authors.forename: Nena
authors.initials: N
authors.lastname: Bonn
authors.forename: Björn F C
authors.initials: BF
authors.lastname: Kafsack
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Shabanowitz
authors.forename: Donald F
authors.initials: DF
authors.lastname: Hunt
authors.forename: Craig
authors.initials: C
authors.lastname: Beeson
authors.forename: Joan
authors.initials: J
authors.lastname: Goverman
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D015551:Autoimmunity; D001667:Binding, Competitive; D000939:Epitopes; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism*; D007108:Immune Tolerance; D051379:Mice; D004676:Myelin Basic Protein / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D004676:Myelin Basic Protein; D010446:Peptide Fragments