A disease-related epitope of Torpedo acetylcholine receptor. Residues involved in I-Ab binding, self-nonself discrimination, and TCR antagonism.
Residues 146-162 of the Torpedo californica acetylcholine receptor alpha-subunit contain the immunodominant T cell epitope for experimental autoimmune myasthenia gravis-susceptible C57BL/6 mice. To develop potential therapeutic peptides, a detailed analysis of the epitope was undertaken. Truncated and substituted synthetic peptides were tested as stimulators of T cell clones and immune lymph node cells. Critical residues spanned positions 151-159. Y151 and V156 were critical for MHC binding. The results indicated a general motif for binding to I-Ab to be an aromatic or hydrophobic residue (preferentially Y or F) at position i followed by an uncharged residue at position (i + 5). Lysine was not tolerated at position (i + 8). Residues D152, K155, S157, and I158 were important T cell contact residues. A peptide corresponding to the murine 146-162 sequence, which differs from the Torpedo sequence at 5 residues, bound to I-Ab but was nonimmunogenic, consistent with the assigned TCR and I-Ab contact residues. These results suggest that tolerance is responsible for the lack of T cell cross-reactivity with the murine acetylcholine receptor. Substituted peptides were tested for the inhibition of T cell clone responses and for TCR antagonism. Although peptides substituted at residues 157 and 158 inhibited most clones, no single peptide could completely inhibit all clones or primed lymph node cells. These findings indicate that antagonist peptides may be useful in inhibiting T cell responses to complex Ag displaying a single immunodominant epitope. Multiple antagonists used in combination may be required for maximum inhibition of the response.
Wall
K A
KA
Department of Medicinal and Biological Chemistry, College of Pharmacy, University of Toledo, OH 43606.
Hu
J Y
JY
Currier
P
P
Southwood
S
S
Sette
A
A
Infante
A J
AJ
D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D001667:Binding, Competitive; D004195:Disease Models, Animal; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007114:Immunization; D016056:Immunodominant Epitopes / Q000235:genetics / Q000378:metabolism; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000209:etiology / Q000628:therapy; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors; D011950:Receptors, Cholinergic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014101:Torpedo / Q000235:genetics / Q000276:immunology*
D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D011950:Receptors, Cholinergic