Although the immunologic role of T cells bearing the conventional αβ T cell receptor (TCR) has been well characterized, little is known about the function of the population of T cells bearing the γδ TCR. Therefore, the role of γδ T cells in the immune response to Mycobacterium tuberculosis (MT) was investigated. The number of TCR γδ cells in the draining lymph nodes of mice immunized with MT was greatly increased in comparison with the number of TCR αβ cells. Three biochemically distinct γδ TCRs were detected. Analyses of cell cycle, of interleukin-2 receptor expression, and of interleukin-2 responsiveness showed that a large proportion of the γδ T cells were activated in vivo. TCR γδ cells responded to solubilized MT antigens in vitro but, in contrast to MT-specific αβ T cells, the response of γδ T cells to MT did not require major histocompatability complex class II recognition. These results provide an example of antigen-specific activation of γδ T cells in vivo and indicate that γδ T cells may have a distinct role in generating a primary immune response to certain microorganisms.