Most cases of latent tuberculosis infection (LTBI) do not cause symptoms during the lifetime of the infected person. Longitudinal analysis of the immune response of healthy Mycobacterium tuberculosis-infected people might, therefore, give insight into the basis of protective immunity. In a longitudinal study, we documented the effect that treatment had on the T cell response to M. tuberculosis antigens in 33 healthy people with LTBI. Preventive treatment of LTBI resulted in a 1.8-fold average increase in the numbers of interferon (IFN)- gamma -producing T cells within 26 +/- 4 days (P = .006), followed by a decrease by the end of the treatment period (82 +/- 6 days; P = .004). There was no significant overall change in the T cell response to any antigen in a control group (n = 8) of patients who elected radiological follow-up. Using live M. tuberculosis strain H37Rv as a stimulant in an enzyme-linked immunospot assay in sensitized individuals, we showed that isoniazid, but not rifampin, led to an increase in the number of IFN- gamma -producing cells. These results suggest that the integrity of the bacterial cell wall is important for M. tuberculosis in avoiding immune recognition by T cells and favor a dynamic model of LTBI.