Immunodominant framework region 3 peptide from TCR V beta 8.2 chain controls murine experimental autoimmune encephalomyelitis.
Previous work has demonstrated the existence of regulatory circuitry that controls response to the dominant determinant Ac1-9 of myelin basic protein (MBP) which is highly restricted in TCR V gene usage to V beta 8.2 and V alpha 2.3. In particular, a CD4+ V beta 14+ regulatory T cell was shown to be a vital component of this circuit. In our work presented here, the peptide specificity of the response to V beta 8.2 peptides was examined. Five overlapping peptides, B1 through B5, were studied for their ability to induce a proliferative response: B2 (21-50), B4 (61-90), and B5 (76-101) each had this capacity in the B10.PL or (SJL x B10.PL)F1 mice. The determinant within the TCR peptide B5 appears dominant, whereas determinants within the B2 and B4 peptides are physiologically cryptic. Furthermore, only B5 could down-regulate the response to MBP Ac1-9 and significantly protect mice from MBP- or Ac1-9-induced EAE, whereas B2 or B4 treatment had no significant effect. Treatment of mice with B5 did not result in generalized deletion or inactivation of V beta 8.2+ T cells. The core residues of the B5 determinant lie within framework region 3 of the V beta 8.2 chain and do not include residues from the joining CDR3 region. Response to B5 was restricted by the I-Au MHC molecule. Furthermore, B5 only induced responses in mice with certain MHC alleles. It is evident that by specifically down-regulating the initial dominant response to Ac1-9, Ag-induced disease can be prevented. These data have implications for understanding induction of TCR-based regulation, as well as relevance to possible therapeutic approaches for oligoclonal responses in human autoimmune diseases.
Kumar
V
V
Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90024.
Tabibiazar
R
R
Geysen
H M
HM
Sercarz
E
E
D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006239:Haplotypes / Q000235:genetics; D016056:Immunodominant Epitopes / Q000276:immunology*; D008285:Major Histocompatibility Complex; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014611:Vaccination
D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta