Highly conserved TCR β 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 callfomlca (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 clonaltty, both in terms of the epltopes recognized and in terms of the diversity of the TCR V_β gene segments used. We now report that all TAChR-reactlve B6 T cell clones which responded to the dominant antigenlc epltope and expressed the dominant TCR V_β6 gene segment exhibited conservation of amlno acid sequence in the VDJ junctional region (CDR3) of the TCR β chain. The conserved sequence motif contained a glutamlc acid residue in the CDR3 of TCR β. Analysis of TCR β sequences from antigen-primed lymph node cells (LNC) showed a similar enrichment for sequences having a glutamlc 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_β gene utilization seen previously is directly related to recognition of the immunodominant peptlde epltope in association with the experimental autoimmune myasthenia gravls-susceptlbllity determining MHC class II molecule I-A^b.