Despite evidence suggesting an anti-Mycobacterium tuberculosis effector function of CD4+ T cells that produce and retain IL-22 in macaques, the general role of IL-22 in tuberculosis infection is still poorly characterized. To explore the immune mechanism in the pathogenesis of tuberculosis in humans, here we evaluated different forms of IL-22 in populations with different tuberculosis infection statuses. We enrolled 156 subjects including 49 patients with pulmonary tuberculosis, 27 patients with tuberculous pleurisy (TPE), 38 individuals with latent tuberculous infection (LTBI) and 42 healthy controls (HC). We found significantly higher IL-22 levels at the tuberculosis infection site than in the peripheral blood as well as higher antigen-specific IL-22 levels in the culture supernatant for patients with active tuberculosis than in healthy controls. The proportions of IL-22 + CD4+ T and IL-22 + CD8+ T cells in patients with active tuberculosis were significantly higher than those in the latent tuberculosis infection group and the healthy control group, based on intracellular cytokine staining. However, surprisingly, we found membrane-bound IL-22+ T cells, including CD4+ T cells and CD8+ T cells, by surface staining, especially in patients with active tuberculosis. Furthermore, the expression of membrane-bound IL-22 significantly decreased after drug therapy. In conclusion, our results suggest that IL-22 has various roles in tuberculosis immune responses. In particular, membrane-bound IL-22+ T cells may play important roles in the human immune response to Mycobacterium.