T uberculosis (TB) presents an interesting paradox: while onethird of the world's population is infected with Mycobacterium tuberculosis, only 5 to 10% of those infected will develop active disease (1,23). This observation suggests that factors other than the mycobacterium play a role in the development of TB. Our understanding of protective immunity to M. tuberculosis infection is incomplete. The immune response to M. tuberculosis involves cells such as monocytes, macrophages, and T lymphocytes that produce cytokines such as CXCL8 (interleukin-8 [IL-8]), IL-12, gamma interferon (IFN-␥), and tumor necrosis alpha (TNF-␣) (16). While hematogenous dissemination occurs in most persons soon after infection, subsequent extrapulmonary TB disease does not (25). Development of extrapulmonary disease could be a result of a breakdown in host immune surveillance, a change in the mycobacteria from a dormant to an active state, or a combination of the two. Discovery of factors that predispose to extrapulmonary disease will advance TB prevention efforts by identifying immune responses that could be boosted by TB vaccines. It will also help identify individuals at increased risk for progression from latent infection to clinical disease, so that more intensive observation and treatment of latent infection can be initiated.Extrapulmonary TB is associated with underlying immune defects. For example, HIV-infected persons are at increased risk of extrapulmonary TB, and this risk increases as the CD4 ϩ T lymphocyte count declines (30). Young children also have an increased incidence of extrapulmonary TB, specifically TB meningitis, presumably due to an immature immune system (31). Our group has previously noted reduced peripheral blood mononuclear cell (PBMC) cytokine production and CD4 ϩ T lymphocytes in HIV-seronegative adults with previous extrapulmonary TB compared to persons with previous pulmonary TB or latent M. tuberculosis infection (2, 38). In a subset of patients from the present study, we also found that persons with previous extrapulmonary TB had increased regulatory T cell frequency and CD4 ϩ lymphocyte activation, indicating possible immune dysregulation (8). However, an evaluation of the sequential activation of innate and adaptive immune responses to M. tuberculosis infection in such patients has not been performed. We therefore assessed in vitro immune responses in persons with previous extrapulmonary TB under several experimental conditions, including one in which autologous monocyte-depleted PBMCs were cocultured with M. tuberculosis-infected host macrophages.