Competition between two MHC binding registers in a single peptide processed from myelin basic protein influences tolerance and susceptibility to autoimmunity.
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.
Seamons
Audrey
A
Department of Immunology, Box 357650, University of Washington, Seattle, WA 98195, USA.
Sutton
Jennifer
J
Bai
Dina
D
Baird
Emily
E
Bonn
Nena
N
Kafsack
Björn F C
BF
Shabanowitz
Jeffrey
J
Hunt
Donald F
DF
Beeson
Craig
C
Goverman
Joan
J
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*
D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D004676:Myelin Basic Protein; D010446:Peptide Fragments