Human lung immunity against Mycobacterium tuberculosis: insights into pathogenesis and protection

Abstract

The study of human pulmonary immunity against Mycobacterium tuberculosis (M.tb) provides a unique window into the biological interactions between the human host and M.tb within the broncho-alveolar microenvironment, the site of natural infection. Studies of bronchoalveolar cells (BACs) and lung tissue evaluate innate, adaptive, and regulatory immune mechanisms that collectively contribute to immunological protection or its failure. In aerogenically M.tb-exposed healthy persons lung immune responses reflect early host pathogen interactions that may contribute to sterilization, the development of latent M.tb infection, or progression to active disease. Studies in these persons may allow the identification of biomarkers of protective immunity before the initiation of inflammatory and disease-associated immunopathological changes. In healthy close contacts of patients with tuberculosis (TB) and during active pulmonary TB, immune responses are compartmentalized to the lungs and characterized by an exuberant helper T-cell type 1 response, which as suggested by recent evidence is counteracted by local suppressive immune mechanisms. Here we discuss how exploring human lung immunity may provide insights into disease progression and mechanisms of failure of immunological protection at the site of the initial host-pathogen interaction. These findings may also aid in the identification of new biomarkers of protective immunity that are urgently needed for the development of new and the improvement of current TB vaccines, adjuvant immunotherapies, and diagnostic technologies. To facilitate further work in this area, methodological and procedural approaches for bronchoalveolar lavage studies and their limitations are also discussed.

Figure 1.

Spectrum of tuberculosis (TB) infection, life cycle of Mycobacterium tuberculosis (M.tb), and the immunopathogenesis of pulmonary tuberculosis. Mycobacteria are inhaled into the lung alveoli (1). Here the infection may be cleared (2) by sterilizing innate or adaptive immune mechanisms (these mechanisms may determine the results of immunodiagnostic tests such as the tuberculin skin test [TST] and IFN-γ release assay [IGRA]). In the remainder (3) the infection may progress to latent M.tb infection (LTBI) (4), or in a small percentage to active TB (5). Some individuals with positive immunodiagnostic tests may, after a transient period of positivity, revert to negative and they presumably may have “acute or chronic resolving infection” (6). Those who have cleared their infection (2) may become reinfected and, depending on prevailing host immunity, may clear their infection (2) or progress to LTBI (4) or active disease (5). **The proportion of persons with positive immunodiagnostic tests who have LTBI is unclear. ^#The proportion of individuals who remain presumably uninfected is variable and will depend on host genetics, strain type, transmission dynamics, and several factors that may attenuate pulmonary-specific host immunity including HIV coinfection, diabetes, malnutrition, immunosuppressive therapy, and so on. ^&The transiency of these responses and the proportion in whom they manifest remain unclear. NK = natural killer; TLR2, 4, and 9 = Toll-like receptors 2, 4, and 9, respectively; Treg = regulatory T cells.

Figure 2.

Presumed cellular and humoral components of adaptive and innate antimycobacterial immunity in the bronchoalveolar spaces. Many of the cellular interactions have not been shown in the bronchoalveolar cells. Cell subpopulations and cytokines that have not been studied in human bronchoalveolar cells are indicated by a question mark (?). Interactions with epithelial cells can be assumed to be far more complex and diversified and humoral factors that may play an important role in the bronchoalveolar spaces have been omitted. DCs = dendritic cells; GM-CSF = granulocyte-macrophage colony-stimulating factor; M.tb = Mycobacterium tuberculosis; TGF-β = transforming growth factor-β; Th1, 2, and 17 = helper T-cell types 1, 2, and 17, respectively; TNF-α = tumor necrosis factor-α; Treg = regulatory T cells.