Induction of T cell responses to an antigenic peptide that is known to bind a major histocompatibility complex molecule is a function of either the T cell receptor (TCR) repertoire or regulatory influences by CD8 or CD4 regulatory T cells. We have tested the hypothesis that a lack of 10 TCR V beta gene segments in V beta a mice may result in an incomplete repertoire of regulatory T cells involved in maintaining peripheral tolerance. Such a hole in the repertoire of regulatory cells could result in expression of T cell responses to antigenic determinants that normally remain undetected in mice with a wild-type repertoire of TCR V beta gene segments. We show here that H-2d mice respond to the peptide 74-96 of hen egg-white lysozyme (HEL) when they are of V beta a haplotype at their TCR locus. The wild-type (V beta b) H-2d mice with their complete set of 20 TCR V beta gene segments fail to respond to HEL 74-96. The 74-96-specific T cell responsiveness was revealed in the wild-type (V beta b) mice when they were treated in vivo with anti-CD8 antibody, implicating the existence of regulatory cells that prevent expression of T cell responses specific for peptide 74-96. This is a demonstration that holes in the regulatory T cell repertoire can, in certain circumstances, become beneficial to the host, for example, in susceptibility against pathogens.