We have shown previously, that production of the macrophage activating cytokine IFN-gamma is depressed in PBMC from patients with newly diagnosed pulmonary tuberculosis. Recent observations further indicate, that this suppression is not only immediate, but also long-lasting as production of IFN-gamma in PBMC from patients did not reach levels found in PBMC from healthy tuberculin reactive controls after successful chemotherapy. These findings suggests, that a fixed defect in T-cell function is responsible for the sustained low T-cell responsiveness during tuberculosis. The loss of antigen responsive T-cells through mechanisms such as apoptosis could explain this prolonged low T-cell IFN-gamma production in tuberculosis. In fact, our preliminary observations show increased spontaneous, as well as enhanced M. tuberculosis-induced apoptosis in T-cells from patients with newly diagnosed tuberculosis. Whether apoptosis in PBMC from patients with tuberculosis is due to modulation of expression of Fas and FasL and/or Bcl-2 and whether cytokines such as TGF-beta and TNF-alpha, which are produced in excess by monocytes from patients with tuberculosis, contribute to the T-cell apoptosis is not known. The above observations and review of the literature support the following hypothesis: Exposure of T-cells to mycobacterial antigens or cytokines during tuberculosis results in alterations in T-cell activation and/or responsiveness leading to increased apoptosis of M. tuberculosis-reactive T-cells. Apoptotic pathways underlie the persistence of defective T-cell function and decreased frequency of M. tuberculosis reactive T-cells and many contribute to the pathogenesis of tuberculosis.
Specific aims to test this hypothesis are: 1. To identify the molecular mechanisms involved in spontaneous and M. tuberculosis-induced apoptosis and to examine the contribution of blood monocytes to this process. 2. To assess the role of apoptosis in the profound immediate and persistent suppression of production of IFN-gamma of patients with tuberculosis.
