Regulation of polyclonal T cell responses by an MHC anchor-substituted variant of myelin oligodendrocyte glycoprotein 35-55.
Analogs of immunogenic peptides containing substitutions at TCR contact residues (altered peptide ligands (APLs)) have been used to manipulate Ag-specific T cell responses in models of autoimmunity, including experimental autoimmune encephalomyelitis. However, recent clinical trials with APL of a myelin basic protein epitope revealed limitations of this therapy. In this study, we demonstrate that individual myelin oligodendrocyte glycoprotein (MOG) 35-55-specific T cell clones responded differentially to a MOG 35-55 APL, raising questions about the ability of peptide analogs containing amino acid substitutions at TCR contact residues to control polyclonal populations of T cells. In contrast, we found that a variant peptide containing a substitution at an MHC anchor residue uniformly affected multiple MOG 35-55-specific clones and polyclonal lines. Stimulation of polyclonal MOG 35-55-specific T cells with an MHC variant peptide resulted in the induction of anergy, as defined by a dramatic reduction in proliferation and IL-2 production upon challenge with wild-type peptide. Furthermore, treatment of T cell lines with this peptide in vitro resulted in a significant reduction in their encephalitogenicity upon adoptive transfer. These results indicate that the use of MHC anchor-substituted peptides may be efficacious in the regulation of polyclonal T cell responses such as those found in EAE.
Ford
Mandy L
ML
Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA.
Evavold
Brian D
BD
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000276:immunology*; D000818:Animals; D002460:Cell Line; D017635:Clonal Anergy / Q000276:immunology; D002999:Clone Cells; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D007114:Immunization; D007279:Injections, Subcutaneous; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation
D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D000949:Histocompatibility Antigens Class II; C474482:I-A(b) antigen, mouse; D008024:Ligands; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55)