Highly conserved TCR beta chain CDR3 sequences among immunodominant acetylcholine receptor-reactive T cells in murine myasthenia gravis.
In C57BL/6 (B6) mice, the T cell response to acetylcholine receptor from Torpedo californica (TAChR) provides a specific antibody response and symptoms of muscular weakness similar to those displayed in the human disease myasthenia gravis. We had found previously that the B6 T cell response to AChR shows limited clonality, both in terms of the epitopes recognized and in terms of the diversity of the TCR V beta gene segments used. We now report that all TAChR-reactive B6 T cell clones which responded to the dominant antigenic epitope and expressed the dominant TCR V beta 6 gene segment exhibited conservation of amino acid sequence in the VDJ junctional region (CDR3) of the TCR beta chain. The conserved sequence motif contained a glutamic acid residue in the CDR3 of TCR beta. Analysis of TCR beta sequences from antigen-primed lymph node cells (LNC) showed a similar enrichment for sequences having a glutamic acid in CDR3, although the overall appearance of the LNC sequences was somewhat more heterogeneous and consistent with a gradual in vitro selection of the subset of TCR found in the T cell clones. As the first example of TCR sequences in this model of myasthenia gravis, these results begin to provide a context for understanding self-non-self discrimination of AChR. In particular, the unusually conserved CDR3 sequence suggests that the conserved V beta gene utilization seen previously is directly related to recognition of the immunodominant peptide epitope in association with the experimental autoimmune myasthenia gravis-susceptibility determining MHC class II molecule I-Ab.
Pierce
J L
JL
Department of Biochemistry, University of Texas Health Science Center at San Antonio 78284.
Zborowski
K A
KA
Kraig
E
E
Infante
A J
AJ
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence; D004247:DNA; D004195:Disease Models, Animal; D005803:Genes, Immunoglobulin; D016056:Immunodominant Epitopes / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology*; D008198:Lymph Nodes; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014101:Torpedo
D016056:Immunodominant Epitopes; D007135:Immunoglobulin Variable Region; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011950:Receptors, Cholinergic; D004247:DNA