Reactivation of latent tuberculosis contributes significantly to the incidence of disease caused by Mycobacterium tuberculosis. The mechanisms involved in the containment of latent tuberculosis are poorly understood. Using the low-dose model of persistent murine tuberculosis in conjunction with MP6-XT22, a monoclonal antibody that functionally neutralizes tumor necrosis factor alpha (TNF-␣), we examined the effects of TNF-␣ on the immunological response of the host in both persistent and reactivated tuberculous infections. The results confirm an essential role for TNF-␣ in the containment of persistent tuberculosis. TNF-␣ neutralization resulted in fatal reactivation of persistent tuberculosis characterized by a moderately increased tissue bacillary burden and severe pulmonic histopathological deterioration that was associated with changes indicative of squamous metaplasia and fluid accumulation in the alveolar space. Analysis of pulmonic gene and protein expression of mice in the low-dose model revealed that nitric oxide synthase was attenuated during MP6-XT22-induced reactivation, but was not totally suppressed. Interleukin-12p40 and gamma interferon gene expression in TNF-␣-neutralized mice was similar to that in control mice. In contrast, interleukin-10 expression was augmented in the TNF-␣-neutralized mice. In summary, results of this study suggest that TNF-␣ plays an essential role in preventing reactivation of persistent tuberculosis, modulates the pulmonic expression of specific immunologic factors, and limits the pathological response of the host.

Although the protective cellular immune response to Mycobacterium tuberculosis requires recruitment of macrophages and T lymphocytes to the site of infection, the signals that regulate this trafficking have not been defined. We investigated the role of C-C chemokine receptor 2 (CCR2)-dependent cell recruitment in the protective response to M. tuberculosis. CCR2 ؊/؊ mice died early after infection and had 100-fold more bacteria in their lungs than did CCR2 ؉/؉ mice. CCR2 ؊/؊ mice exhibited an early defect in macrophage recruitment to the lung and a later defect in recruitment of dendritic cells and T cells to the lung. CCR2 ؊/؊ mice also had fewer macrophages and dendritic cells recruited to the mediastinal lymph node (MLN) after infection. T cell migration through the MLN was similar in CCR2 ؊/؊ and CCR2 ؉/؉ mice. However, T cell priming was delayed in the MLNs of the CCR2 ؊/؊ mice, and fewer CD4 ؉ and CD8 ؉ T cells primed to produce IFN-␥ accumulated in the lungs of the CCR2 ؊/؊ mice. These data demonstrate that cellular responses mediated by activation of CCR2 are essential in the initial immune response and control of infection with M. tuberculosis.

؊/؊ mice survive with substantially fewer macrophages in the low-dose models implies that the immune response to low-dose M. tuberculosis infection in mice is more robust than necessary to control the infection. Finally, these data demonstrate that, in cases of infectious disease in knockout models, clear phenotypes may not be evident when one is solely evaluating bacterial numbers and survival. Functional assays may be necessary to reveal roles for components of the multifactorial immune system.

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