Innate immunity to Mycobacterium tuberculosis

Abstract

The different manifestations of infection with Mycobacterium tuberculosis reflect the balance between the bacillus and host defense mechanisms. Traditionally, protective immunity to tuberculosis has been ascribed to T-cell-mediated immunity, with CD4(+) T cells playing a crucial role. Recent immunological and genetic studies support the long-standing notion that innate immunity is also relevant in tuberculosis. In this review, emphasis is on these natural, innate host defense mechanisms, referring to experimental data (e.g., studies in gene knockout mice) and epidemiological, immunological, and genetic studies in human tuberculosis. The first step in the innate host defense is cellular uptake of M. tuberculosis, which involves different cellular receptors and humoral factors. Toll-like receptors seem to play a crucial role in immune recognition of M. tuberculosis, which is the next step. The subsequent inflammatory response is regulated by production of pro- and anti-inflammatory cytokines and chemokines. Different natural effector mechanisms for killing of M. tuberculosis have now been identified. Finally, the innate host response is necessary for induction of adaptive immunity to M. tuberculosis. These basic mechanisms augment our understanding of disease pathogenesis and clinical course and will be of help in designing adjunctive treatment strategies.

FIG. 1.

Chronological events after inhalation of M. tuberculosis. After inhalation of M. tuberculosis (MTB) droplet nuclei, several scenarios may follow. Mycobacteria may be destroyed by alveolar macrophages, in which case no real infection will take place. Alternatively, M. tuberculosis may not be immediately killed, and so a primary complex consisting of a small infiltrate and a draining lymph node will develop. Small calcifications may be seen on radiographic examination and the PPD skin test, as a marker of an M. tuberculosis-specific T-cell response, becomes positive. Most often, infection is stabilized at this point. In a minority of cases active disease now develops (primary tuberculosis [TB]), either in the lungs or anywhere else after hematogenous dissemination of M. tuberculosis. Months or years afterwards, usually under conditions of failing immune surveillance, latent infection may reactivate (postprimary TB).

FIG. 2.

Phagocytosis and immune recognition of M. tuberculosis. Various receptors have been identified for phagocyosis of M. tuberculosis (MTB) by macrophages and dendritic cells: complement receptors are primarily responsible for uptake of opsonized M. tuberculosis; MRs and scavenger receptors for uptake of nonopsonized M. tuberculosis. TLRs play a central role in immune recognition of M. tuberculosis. In the context of CD14, TLR2 binds lipoarabinomannan, a heterodimer of TLR2 and TLR6 binds a 19-kDa M. tuberculosis lipoprotein, TLR4 binds to an undefined heat-labile cell-associated factor, and (possibly) TLR9 binds to M. tuberculosis DNA. After binding to TLRs, common signalling pathways lead to cell activation and cytokine production. TLRs are expressed not only at the cell surface but also in phagosomes; therefore, immune activation may occur with or without phagocytosis. On the other hand, phagocytosis alone probably does not lead to immune activation without the involvement of TLRs.

FIG. 3.

Inflammatory response of phagocytic cells upon activation with M. tuberculosis. Immune recognition of M. tuberculosis by macrophages and dendritic cells is followed by an inflammatory response with a crucial role for cytokine production. Initial events in this cellular response include nonspecific host defense mechanisms, which may lead to early killing or containment of infection. In addition, various cellular products, including cytokines and cell surface markers, are involved in these processes as depicted in the figure (in italics). The anti-inflammatory cytokines (see text [“Anti-Inflammatory Cytokines”]) are not represented in this picture.

FIG. 4.

Cytokines and cytokine receptors involved in type I immunity in tuberculosis. A major effector mechanism of cell-mediated immunity in tuberculosis is the activation of M. tuberculosis-infected macrophages by IFN-γ. IFN-γ is produced by NK cells and different T-cell subsets, and its production is regulated by TNF-α, IL-1β, IL-12, IL-18, and possibly IL-15, all released from activated macrophages and dendritic cells. Ag, antigen.