Two-domain MHC class II molecules form stable complexes with myelin basic protein 69-89 peptide that detect and inhibit rat encephalitogenic T cells and treat experimental autoimmune encephalomyelitis.
We designed and expressed in bacteria a single-chain two-domain MHC class II molecule capable of binding and forming stable complexes with antigenic peptide. The prototype "beta1alpha1" molecule included the beta1 domain of the rat RT1.B class II molecule covalently linked to the amino terminus of the alpha1 domain. In association with the encephalitogenic myelin basic protein (MBP) 69-89 peptide recognized by Lewis rat T cells, the beta1alpha1/MBP-69-89 complex specifically labeled and inhibited activation of MBP-69-89 reactive T cells in an IL-2-reversible manner. Moreover, this complex both suppressed and treated clinical signs of experimental autoimmune encephalomyelitis and inhibited delayed-type hypersensitivity reactions and lymphocyte proliferation in an Ag-specific manner. These data indicate that the beta1alpha1/MBP-69-89 complex functions as a simplified natural TCR ligand with potent inhibitory activity that does not require additional signaling from the beta2 and alpha2 domains. This new class of small soluble polypeptide may provide a template for designing human homologues useful in detecting and regulating potentially autopathogenic T cells.
Burrows
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GG
Veterans Affairs Medical Center, Department of Neurology, Oregon Health Sciences University, Portland 97201, USA. ggb@ohsu.edu
Bebo
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Adlard
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Vandenbark
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Offner
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D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000138:chemical synthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D046911:Macromolecular Substances; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins