Protection against tuberculosis: cytokines, T cells, and macrophages

Abstract

Tuberculosis remains a major health problem, with two million deaths and eight million new cases annually. At the same time, two billion people (one third of the total world population) are infected with the aetiological agent, Mycobacterium tuberculosis. Of these, fewer than 10% ever develop disease, although the pathogen is not eradicated but rather contained in discrete lesions. Hence, the immune system is highly effective in containing the pathogen, but fails to eradicate it. Disease typically develops through reactivation once the immune system is weakened. The immune response to M tuberculosis is T cell dependent. It comprises not only the conventional CD4 and CD8 T cells, but also gammadelta T cells and CD1 restricted T cells. gammadelta T cells recognise phospholigands and no presentation molecules are known thus far. CD1 restricted T cells recognise glycolipids, which are highly abundant components of the mycobacterial cell wall. Although different T cells are required for optimum protection, the immune mechanisms known to have a role in acquired resistance can be associated with two major mechanisms: (a) activation of macrophages by cytokines; (b) direct cytolytic activity. In vivo granuloma formation, which is central to protection, is induced and sustained by cytokines. Mycobacteria are contained within granulomas and in this way are prevented from spreading all over the body.

Figures

Figure 1

Different outcomes of infection with M tuberculosis, different T cell populations involved in protection, and major anti-mycobacterial effector mechanisms of macrophages. This scheme firstly depicts the different outcomes of tuberculosis in healthy and immunocompromised subjects. Secondly, the figure shows the different T cell populations and their major T cell effector mechanisms in the control of disease. Thirdly, the figure shows anti-mycobacterial effector mechanisms of activated macrophages. (Reproduced from Nature Reviews Immunology (vol 1:20–30). Reprinted by permission from Nature Reviews Immunology (2001;1:20–30). Copyright © 2001 Macmillan Magazines Ltd.)

Figure 2

Development of granulomatous lesions in tuberculosis. Promptly after infection, T cells and macrophages are attracted to the site of mycobacterial implantation. There, granulomatous lesions develop. As long as the immune response is competent, the lesions will contain bacteria. These productive granulomas represent a focus of highly dynamic interactions between different T cell populations, macrophages of different maturation stages, and dendritic cells. Once immunity weakens, the balance is tipped and the granuloma can no longer contain mycobacteria. Rather, the granulomatous lesion liquefies and bacteria are released to different tissue sites, different organs, and to the environment. Active disease develops and the patient becomes contagious. (For further details see ref 8.)

Figure 3

Different antigen presentation pathways in tuberculosis. Mycobacterial antigens reside in the early phagosome. There, their proteins have ready access to MHC class II processing, resulting in potent CD4 T cell stimulation. Phospholigands are produced by these mycobacteria, which stimulate γδ T cells in the absence of known antigen presentation molecules. Presentation of proteins by MHC class I and of glycolipids by CD1 is more complex and probably requires cross priming. Mycobacteria infected macrophages undergo apoptosis. Resulting extracellular vesicles carry antigens to bystander dendritic cells. Uptake of these vesicles results in glycolipid presentation through CD1 and protein presentation through MHC class I. This two cell mechanism can explain stimulation of MHC class I restricted CD8 T cells and of CD1 restricted T cells. (Reproduced from Nature Reviews Immunology (vol 1:20–30). Reprinted by permission from Nature Reviews Immunology (2001;1:20–30). Copyright © 2001 Macmillan Magazines Ltd.)