We investigated whether the proinflammatory T cell cytokines IL-17 and IL-22 are induced by human mycobacterial infection. Remarkably,> 20% of specific cytokine-producing CD4+ T cells in peripheral blood of healthy, mycobacteria-exposed adults expressed IL-17 or IL-22. Specific IL-17-and IL-22-producing CD4+ T cells were distinct from each other and from Th1 cytokine-producing cells. These cells had phenotypic characteristics of long-lived central memory cells. In patients with tuberculosis disease, peripheral blood frequencies of these cells were reduced, whereas bronchoalveolar lavage fluid contained higher levels of IL-22 protein compared with healthy controls. IL-17 was not detected in this fluid, which may be due to suppression by Th1 cytokines, as PBMC IL-17 production was inhibited by IFN-γ in vitro. However, Th1 cytokines had no effect on IL-22 production in vitro. Our results imply that the magnitude and complexity of the anti-mycobacterial immune response have historically been underestimated. IL-17-and IL-22-producing CD4+ T cells may play important roles in the human immune response to mycobacteria.