Discrete T Cell Populations with Specificity for a Neo-Self-Antigen Bear Distinct Imprints of Tolerance

Mice expressing the Torpedo acetylcholine receptor α-chain as a neo-self-Ag exhibit a reduced frequency of T cells responding to the immunodominant epitope Tα146–162 indicating a degree of tolerance. We characterized tolerance induction in these animals by analyzing the residual Tα146–162-responsive T cell population and comparing it to that of nontransgenic littermates. Using CD4 high sorting, we isolated the vast majority of Ag-reactive T cells from both strains of mice. Quantitative studies of the CD4 high populations in transgenic mice following immunization with Tα146–162 revealed a diminished expansion of cells expressing the canonical TCRBV6 but not other TCRBV gene segments when compared with nontransgenic littermates. In addition, CD4 high cells from transgenic mice were functionally hyporesponsive to Tα146–162 in terms of proliferation and cytokine secretion regardless of TCRBV gene segment use. TCR sequence analysis of transgenic Vβ6 + CD4 high cells revealed a reduced frequency of cells expressing a conserved motif within the TCRβ CDR3. Thus, the canonical Tα146–162 responsive, Vβ6 + population demonstrates both quantitative and qualitative deficits that correlate with an altered TCR repertoire whereas the non-Vβ6 population in transgenic mice exhibits only a reduction in peptide responsiveness, a qualitative defect. These data demonstrate that discrete autoreactive T cell populations with identical peptide/MHC specificity in Torpedo acetylcholine receptor-α-transgenic animals bear distinct tolerance imprints.