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.