Continuous and discontinuous cigarette smoke exposure differentially affects protective Th1 immunity against pulmonary tuberculosis.

Pulmonary tuberculosis (TB), caused by Mycobacterium tuberculosis, is the leading cause of death due to a bacterial pathogen. Emerging epidemiologic evidence suggests that the leading risk factor associated with TB mortality is cigarette smoke exposure. Despite this, it remains poorly understood what is the effect of cigarette smoke exposure on anti-TB immunity and whether its potential detrimental effect can be reversed by cigarette smoking cessation. In our current study, we have investigated the impact of both continuous and discontinuous cigarette smoke exposure on the development of anti-mycobacterial type 1 immunity in murine models. We find that while continuous cigarette smoke exposure severely impairs type 1 immunity in the lung, a short-term smoking cessation allows rapid restoration of anti-mycobacterial immunity. The ability of continuous cigarette smoke exposure to dampen type 1 protective immunity is attributed locally to its affects on innate immune cells in the lung. Continuous cigarette smoke exposure locally, by not systemically, impairs APC accumulation and their production of TNF, IL-12, and RANTES, blunts the recruitment of CD4+IFN-γ+ T cells to the lung, and weakens the formation of granuloma. On the other hand, smoking cessation was found to help restore type 1 immunity by rapidly improving the functionality of lung APCs, enhancing the recruitment of CD4+IFN-γ+ T cells to the lung, and promoting the formation of granuloma. Our study for the first time demonstrates that continuous, but not discontinuous, cigarette smoke exposure severely impedes the lung expression of anti-TB Th1 immunity via inhibiting innate immune activation and lung T cell recruitment. Our findings thus suggest cigarette smoking cessation to be beneficial to the control of pulmonary TB.

Immunization strategies against pulmonary tuberculosis: considerations of T cell geography.

Pulmonary tuberculosis (TB) remains a global health concern with an astounding 9 million new cases and 2 million deaths per year. This leading infectious cause of death remains highly prevalent with one third of the world's population latently infected with Mycobacterium tuberculosis (M.tb) despite routine vaccination against TB in endemic areas. The only approved TB vaccine is the Bacille Calmette-Guerin (BCG), which provides protection against childhood miliary tuberculosis and has been administered intradermally in humans for almost a century. While effective in preventing disseminated forms of TB, the BCG has variable efficacy in providing protection against pulmonary TB. Therefore, the BCG has been unable to control the instance of adult pulmonary TB which constitutes the global disease burden. Despite the fact that mechanisms underlying the lack of pulmonary protection provided by the BCG remain poorly understood, it remains the "Gold Standard" for vaccine-mediated protection against M.tb and will continue to be used for the foreseeable future. Therefore, continued effort has been placed on understanding the mechanisms behind the failure of BCG to provide sufficient protection against M.tb in the lung and to design new vaccines to be used in conjunction with the BCG as boost strategies to install protective immunity at the site of infection. Growing evidence supports that the route of immunization dictates the geographical location of TB-reactive T cells, and it is this distribution which predicts the protective outcome of such vaccine-elicited immunity. Such vaccines that are able to localize TB-reactive T cells to the lung and airway mucosa are thought to fill the "immunological gap" in the lung that is required for enhanced protection against M.tb infection. This chapter focuses on the critical importance of T cell geography when designing new immunization strategies against pulmonary TB.

Within the Enemy's Camp: contribution of the granuloma to the dissemination, persistence and transmission of Mycobacterium tuberculosis.

Pulmonary tuberculosis, caused by Mycobacterium tuberculosis (M.tb) represents a leading global health concern, with 8.7 million newly emerging cases, and 1.4 million reported deaths annually. Despite an estimated one third of the world's population being infected, relatively few infected individuals ever develop active clinical disease. The ability of the host to remain latently infected while preventing disease is thought to be due to the generation of a robust type 1 immune response in the lung, capable of controlling, but not clearing, M.tb. A key feature of the type 1 immune response to M.tb is the formation of immune cellular aggregates termed granuloma. The granuloma structure has long been considered a hallmark of host's protective response toward M.tb. Historically, a correlative relationship between granuloma formation/maintenance and bacterial control has been seen in models where disrupted granuloma formation or structure was found to be fatal. Despite this established relationship much about the granuloma's role in M.tb immunity remains unknown. Recent publications suggest that the granuloma actually aids the persistence of M.tb and that the development of a necrotic granuloma is essential to person-to-person transmission. Our group and others have recently demonstrated that enclosed within the granuloma is a population of immunologically altered antigen-presenting cells and T lymphocyte populations. Of note, the ability of these populations to produce type 1 cytokines such as interferon-gamma, and bactericidal products including nitric oxide, are significantly reduced, while remaining competent to produce high levels immunosuppressive interleukin-10. These observations indicate that although the chronic granuloma represents a highly unique environment, it is more similar to that of a tumor than an active site of bacterial control. In this review we will explore what is known about this unique environment and its contribution to the persistence of M.tb.

Pulmonary mycobacterial granuloma increased IL-10 production contributes to establishing a symbiotic host-microbe microenvironment.

The granuloma, a hallmark of host defense against pulmonary mycobacterial infection, has long been believed to be an active type 1 immune environment. However, the mechanisms regarding why granuloma fails to eliminate mycobacteria even in immune-competent hosts, have remained largely unclear. By using a model of pulmonary Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection, we have addressed this issue by comparing the immune responses within the airway luminal and granuloma compartments. We found that despite having a similar immune cellular profile to that in the airway lumen, the granuloma displayed severely suppressed type 1 immune cytokine but enhanced chemokine responses. Both antigen-presenting cells (APCs) and T cells in granuloma produced fewer type 1 immune molecules including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and nitric oxide. As a result, the granuloma APCs developed a reduced capacity to phagocytose mycobacteria and to induce T-cell proliferation. To examine the molecular mechanisms, we compared the levels of immune suppressive cytokine IL-10 in the airway lumen and granuloma and found that both granuloma APCs and T cells produced much more IL-10. Thus, IL-10 deficiency restored type 1 immune activation within the granuloma while having a minimal effect within the airway lumen. Hence, our study provides the first experimental evidence that, contrary to the conventional belief, the BCG-induced lung granuloma represents a symbiotic host-microbe microenvironment characterized by suppressed type 1 immune activation.

Respiratory mucosal immunization with adenovirus gene transfer vector induces helper CD4 T cell-independent protective immunity.

BACKGROUND: Virus-vectored vaccine is a powerful activator of CD8 T cell-mediated immunity and is especially amenable to respiratory mucosal immunization, offering hopes for use in humans with diminished helper CD4 T cell function. However, whether virus-mediated mucosal immunization can produce immune protective CD8 T cells without the CD4 T cell help remains to be investigated. METHODS: We used a replication-deficient adenovirus vector expressing an Mycobacterium tuberculosis antigen Ag85A for intranasal vaccination and evaluated its effect on CD8 T cell activation and protection in mice depleted of CD4 T cells. RESULTS: Intranasal vaccination of CD4 T cell-depleted mice led to suboptimal generation of Ag-specific tetramer(+) or interferon (IFN)-gamma-producing CD8 T cells in the lung and spleen but this was observed mainly at the early time after vaccination. Reduced CD8 T cell priming was also accompanied by decreased CD8 T cell responses (CTL). Nevertheless, the ratio of Ag-specific CD8 T cells to IFN-gamma-producing CD8 T cells in CD4 T cell-depleted hosts remained comparable to that in CD4 T cell-competent hosts. Furthermore, the 'unhelped' CD8 T cells also displayed a similar immune phenotype as the 'helped' counterparts. The animals with 'unhelped' CD8 T cells were as well-protected from pulmonary M. tuberculosis challenge as those with 'helped' CD8 T cells in the absence of CD4 T cells. CONCLUSIONS: The data obtained in the present study suggest that the fully immune protective CD8 T cells can still be generated by respiratory mucosal viral-mediated immunization without CD4 T cells and that CD8 T cells, 'helped' or 'unhelped', can confer significant protection against pulmonary tuberculosis independent of CD4 T cells.