The resurgence of tuberculosis worldwide has intensified research efforts directed at examining the host defense and pathogenic mechanisms operative in Mycobacterium tuberculosis infection. This review summarizes our current understanding of the host immune response, with emphasis on the roles of macrophages, T cells, and the cytokine/chemokine network in engendering protective immunity. Specifically, we summarize studies addressing the ability of the organism to survive within macrophages by controlling phagolysosome fusion. The recent studies on Toll-like receptors and the impact on the innate response to M. tuberculosis are discussed. We also focus on the induction, specificity, and effector functions of CD4(+) and CD8(+) T cells, and the roles of cytokines and chemokines in the induction and effector functions of the immune response. Presentation of mycobacterial antigens by MHC class I, class II, and CD1 as well as the implications of these molecules sampling various compartments of the cell for presentation to T cells are discussed. Increased attention to this disease and the integration of animal models and human studies have afforded us a greater understanding of tuberculosis and the steps necessary to combat this infection. The pace of this research must be maintained if we are to realize an effective vaccine in the next decades.

Immunology of tuberculosis.

Tuberculosis remains one of the major infectious causes of morbidity and mortality in the world, yet the mechanisms by which macrophages defend against Mycobacterium tuberculosis have remained obscure. Results from this study show that murine macrophages, activated by interferon gamma, and lipopolysaccharide or tumor necrosis factor alpha, both growth inhibit and kill M. tuberculosis. This antimycobacterial effect, demonstrable both in murine macrophage cell lines and in peritoneal macrophages of BALB/c mice, is independent of the macrophage capacity to generate reactive oxygen intermediates (ROI). Both the ROI-deficient murine macrophage cell line D9, and its ROI-generating, parental line J774.16, expressed comparable antimycobacterial activity upon activation. In addition, the oxygen radical scavengers superoxide dismutase (SOD), catalase, mannitol, and diazabicyclooctane had no effect on the antimycobacterial activity of macrophages. These findings, together with the results showing the relative resistance of M. tuberculosis to enzymatically generated H2O2, suggest that ROI are unlikely to be significantly involved in killing M. tuberculosis. In contrast, the antimycobacterial activity of these macrophages strongly correlates with the induction of the L-arginine-dependent generation of reactive nitrogen intermediates (RNI). The effector molecule(s) that could participate in mediating this antimycobacterial function are toxic RNI, including NO, NO2, and HNO2, as demonstrated by the mycobacteriocidal effect of acidified NO2. The oxygen radical scavenger SOD adventitiously perturbs RNI production, and cannot be used to discriminate between cytocidal mechanisms involving ROI and RNI. Overall, our results provide support for the view that the L-arginine-dependent production of RNI is the principal effector mechanism in activated murine macrophages responsible for killing and growth inhibiting virulent M. tuberculosis.

https://rupress.org/jem/article-pdf/175/4/1111/1102432/1111.pdf

Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages.

The attenuated strain of Mycobacterium bovis bacille Calmette–Guerin (BCG) is the most widely used vaccine in the world. In most children, inoculation of live BCG vaccine is harmless although it oc...

https://www.nejm.org/doi/pdf/10.1056/NEJM199612263352604

Interferon-gamma-receptor deficiency in an infant with fatal bacille calmette-guerin infection

MTB ranks as the first worldwide pathogen latently infecting one third of the population and the second leading cause of death from a single infectious agent, after the human immunodeficiency virus (HIV). The development of vigorous and apparently appropriate immune response upon infection with M.tuberculosis in humans and experimental animals conflict with failure to eradicate the pathogen itself and with its ability to undergo clinical latency from which it may exit. From a clinical standpoint, our views on MTB infection may take advantage from updating the overall perspective, that has quite changed over the last decade, following remarkable advances in our understanding of the manipulation of the immune system by M.tuberculosis and of the role of innate components of the immune response, including macrophages, neutrophils, dendritic cells and NK cells in the initial spread of MTB and in its exit from latency. Scope of this review is to highlight the the major mechanisms of MTB escape from immune control and to provide a supplementary translational perspective for the interpretation of innate immune mechanisms with particular impact on clinical aspects.

/pdf/immunology-of-tuberculosis-55xecqgi4x.pdf

Immunology of Tuberculosis

Wild-type (WT) and targeted-mutant mice incapable of making αβ T cells, γδ T cells, class I major histocompatibility complex (MHC), class II MHC, interferon (IFN)-γ, or inducible nitric oxide synthase (NOS2), were infected with Mycobacterium tuberculosis (Mtb) by aerosol, and monitored over time for their ability to (a) control infection, (b) develop histopathology at sites of infection, and (c) survive. WT mice acquired the ability to control and to hold infection at a stationary level from day 20 on. This was associated with the development of a macrophage-dominated alveolitis at sites of infection, with increased synthesis of IFN-γ and NOS2 mRNA, and with an median survival time (MST) of 258.5 d. In the absence of αβ T cells, Mtb grew progressively and rapidly to induce a necrotic, neutrophil-dominated lung pathology that killed mice with an MST of 48 d. In the absence of CD4-mediated immunity (class II−/− mice), progressive bacterial growth continued in the lungs and in other organs beyond day 20, resulting in an MST of 77 d. By contrast, in the absence of CD8 T cell–mediated immunity, lung infection was controlled at a 1 log higher stationary level that induced a similar histopathologic response to that of WT mice, and resulted in an MST of 232 d.

https://rupress.org/jem/article-pdf/193/3/271/1133424/001848.pdf

The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice.

Tuberculosis and leprosy remain two of the world's most significant diseases. Immunity involves the activation of macrophages by lymphokines but the details are unknown because there has been no objective assay for the relevant effector function using human pathogens. We previously reported the use of tritiated-uracil uptake by surviving mycobacteria as a measure of the anti-mycobacterial effect of human monocytes. We describe here the use of a modification of this assay to measure control of the proliferation of Mycobacterium tuberculosis in murine peritoneal macrophages. A bacteriostatic effect can be induced in macrophages infected with M. tuberculosis, by adding small numbers of Ly 1 +2- T cells from in vitro lines derived from immunized mice. The phenomenon is dependent on compatibility at the I-A locus of the major histocompatibility complex (MHC) and mediated by soluble factors. Such T cells also recognise and activate macrophages infected with other mycobacterial pathogens. Thus, T cells recognising shared mycobacterial antigens are active. The findings have implications for MHC linked susceptibility to mycobacterioses and the hypothesized ability of cross-reactive environmental mycobacteria to abrogate or pre-empt the protective efficacy of subsequent BCG vaccination.

I-A restricted activation by T cell lines of anti-tuberculosis activity in murine macrophages.

I-a restricted activation by t-cell lines of anti-tuberculosis activity in murine macrophages

When cultured in 20% heat-inactivated human serum, human monocytes from seven donors were not on average significantly different from non-activated murine peritoneal cells (cultured simultaneously and in an identical manner) in their ability to inhibit BCG and, when calculated relative to growth of bacilli in the same medium without macrophages, to enhance the growth of Mycobacterium tuberculosis. Recombinant gamma-interferon caused marked inhibition of virulent M. tuberculosis by murine (BALB/c) peritoneal macrophages. This effect was seen, whether the cells were cultured in 10% fetal calf serum or in 20% heat-inactivated normal human serum, with or without the addition of iron supplements. However, unlike murine cells, the addition of crude lymphokine or recombinant gamma-interferon to human monocytes caused only weak inhibition of M. tuberculosis, and in some instances, gamma-interferon caused enhancement of growth of the bacilli. Monocytes were only slightly more effective if precultured for 4-8 days before the addition of the activating stimulus. This relative failure to develop anti-mycobacterial mechanisms occurred in spite of the activation of the cells as shown by a massive increase in reduction of nitro-blue tetrazolium inducible by phorbol myristate acetate.

Activation of macrophages to inhibit proliferation of mycobacterium-tuberculosis - comparison of the effects of recombinant gamma-interferon on human-monocytes and murine peritoneal-macrophages

We sought to protect CBA mice against tuberculosis using in vivo transfer of a T-cell line previously shown to be capable of I-A-restricted recognition of peritoneal macrophages infected in vitro with Mycobacterium tuberculosis. This line induces total bacteriostasis in vitro. In mice that received 500 rads of irradiation 48 h before infection, the T-cell line caused significant prolongation of life when given intravenously with a challenge dose of 5 x 10(6) organisms. Similar experiments with two other T-cell lines showed that these lines offered no protection. Bacterial load at the time of death was inversely related to the time of survival. Thus, death occurred at a lower bacterial load in adoptively protected mice, implying the contribution of an immunopathological component in these animals. The protective T-cell line, which was CD4+ CD8-, had no effect on the rate of growth of strain BCG in CBA nu/nu mice or M. tuberculosis in fully T-cell-deprived mice. This could indicate that CD8+ cells play a role in this system or that there is a need for the recruitment of interleukin 2-producing cells in the recipient. Experiments with monoclonal antibodies to selectively deplete T-cell subsets in normal CBA mice showed that depletion of CD4+ cells strikingly shortened survival, whereas depletion of CD8+ cells did not. However, CD8-depleted mice died with a lower bacterial load than those found in nondepleted controls, and the lesions in CD8-depleted mice were histopathologically distinct. These results suggest that the CD8+ cells either down-regulate bacteriostasis or cause immunopathology in this model and that it is the CD4+ cells that are the major protective subset in long-term protection experiments.

T-cell-mediated protection of mice against virulent Mycobacterium tuberculosis.

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I-A restricted activation by T cell lines of anti-tuberculosis activity in murine macrophages.

I-a restricted activation by t-cell lines of anti-tuberculosis activity in murine macrophages

Activation of macrophages to inhibit proliferation of mycobacterium-tuberculosis - comparison of the effects of recombinant gamma-interferon on human-monocytes and murine peritoneal-macrophages

T-cell-mediated protection of mice against virulent Mycobacterium tuberculosis.