Mice of strain B6, but not AKR/J, respond to immunization with Torpedo acetylcholine receptor (AChR) by manifesting in vitro an Ag-specific T lymphocyte proliferative response. Our analysis of (AKR x B6)F1 mice reveals that the T cell unresponsiveness of AKR/J is inherited as a dominant trait, possibly associated with expression of the Mls-1a allele. Mice derived from backcrossing (AKR x B6)F1 x B6 were selected for H-2b homozygosity and were classified as Mls-1a or Mls-1b according to the relative numbers of peripheral blood T cells that expressed the TCR V beta 6 gene product. After challenge by injection with AChR in CFA, lymph node cells from mice classified as having less than 2% of V beta 6+ peripheral T cells had low responsiveness to AChR, whereas mice with greater than 7% V beta 6+ peripheral T cells had high T cell responsiveness to AChR. These results are consistent with the notion that regulation of the T cell repertoire by Mls loci may be a determinant of susceptibility to autoimmunity.