Tuberculosis (TB) remains a worldwide leading cause of death among infectious diseases. Development of safer and more efficacious vaccines requires a basic understanding of the protective mechanisms induced by BCG. Here we show that vaccination of cattle with BCG induces CD8+gamma/deltaTCR-CD45RO+ T-cells that can produce IFN-gamma, up-regulate transcription and expression of perforin, lyse BCG-infected monocyte-derived macrophages (MoMvarphi) and contribute to a reduction in the number of intracellular mycobacteria. We also observed BCG-induced CD8+ responses in vivo. After infection of cattle with Mycobacterium bovis, CD8+gamma/deltaTCR-CD45RO+ cells responded more strongly to M. bovis-infected MoMvarphi than to BCG-infected MoMvarphi. These results indicate that the antigen-specific CD8+ memory response resides in the CD8+gamma/deltaTCR-CD45RO+ cell population.