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Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Toll-like receptors

Nature Reviews Microbiology volume 8, pages 296–307 (2010)Cite this article

Subjects

Key Points

  • Mycobacterium tuberculosis survives in the host in antigen-presenting cells (APCs) such as macrophages and dendritic cells.

  • APCs present antigens in association with major histocompatibility complex (MHC) class II molecules to stimulate CD4+ T cells, and this process is essential for containing M. tuberculosis infection.

  • Immune evasion allows M. tuberculosis to establish persistent or latent infection in APCs.

  • M. tuberculosis infection of macrophages results in Toll-like receptor 2 (TLR2)-dependent inhibition of MHC class II transactivator (CIITA) and MHC class II molecule expression and of MHC class II antigen presentation, providing a mechanism for immune evasion.

  • The TLR2-dependent reduction of antigen presentation might reflect a general mechanism of negative-feedback regulation that prevents excessive T cell-mediated inflammation and that M. tuberculosis has subverted for the purposes of immune evasion.

  • Inhibition of antigen presentation creates a niche for M. tuberculosis survival in infected APCs and for its evasion of recognition by CD4+ T cells.

Abstract

Mycobacterium tuberculosis survives in antigen-presenting cells (APCs) such as macrophages and dendritic cells. APCs present antigens in association with major histocompatibility complex (MHC) class II molecules to stimulate CD4+ T cells, and this process is essential to contain M. tuberculosis infection. Immune evasion allows M. tuberculosis to establish persistent or latent infection in macrophages and results in Toll-like receptor 2 (TLR2)-dependent inhibition of MHC class II transactivator expression, MHC class II molecule expression and antigen presentation. This reduction of antigen presentation might reflect a general mechanism of negative-feedback regulation that prevents excessive T cell-mediated inflammation and that M. tuberculosis has subverted to create a niche for survival in infected macrophages and evasion of recognition by CD4+ T cells.

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Figure 1: The host response to Mycobacterium tuberculosis infection.
Figure 2: Toll-like receptor 2 ligands expressed by Mycobacterium tuberculosis.
Figure 3: Major histocompatibility complex class II synthesis and function.
Figure 4: Inhibition of major histocompatibility complex class II by Mycobacterium tuberculosis through Toll-like receptor signalling.
Figure 5: The different responses of macrophages and dendritic cells to Toll-like receptor signalling.

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Acknowledgements

Research in the authors' laboratories is supported by US National Institutes of Health grants AI035726, AI034343 and AI069085 to C.V.H. and grants HL055967 and AI027243 to W.H.B.

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Authors and Affiliations

  1. Department of Pathology, Case Western Reserve University,

    Clifford V. Harding & W. Henry Boom

  2. Center for AIDS Research, University Hospitals Case Medical Center,

    Clifford V. Harding & W. Henry Boom

  3. Tuberculosis Research Unit, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, 44106–7288, Ohio, USA

    W. Henry Boom

  4. Division of Infectious Diseases, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, 44106–7288, Ohio, USA

    W. Henry Boom

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DATABASES

Entrez Genome Project

Escherichia coli

Mycobacterium bovis bacille Calmette—Guérin

Mycobacterium smegmatis

Mycobacterium tuberculosis

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Glossary

CD4+ T cell

A T cell that expresses the CD4 receptor. These cells recognize antigens that are presented on the surface of host cells by MHC class II molecules.

CD8+ T cell

A T cell that expresses the CD8 receptor. These cells recognize antigens that are presented on the surface of host cells by MHC class I molecules, leading to host cell destruction, and are therefore also known as cytotoxic T cells.

γδ T cell

A T cell that expresses the γδ T cell receptor. Although the exact function of γδ T cells is unknown, it has been suggested that mucosal γδ T cells are involved in innate immune responses

Granuloma

An organized structure that comprises lymphocytes, macrophages, neutrophils and, sometimes, fibroblasts and that often has a necrotic centre, which arises in response to continued antigenic stimulation in the presence of macrophages (as occurs, for example, in M. tuberculosis infection).

Toll-like receptor

A membrane-spanning protein that recognizes conserved ligands on pathogens, such as flagellin, lipopolysaccharide or DNA, and that is therefore a key recognition molecule in the host innate immune response.

Tuberculin skin test

A method of diagnosing M. tuberculosis infection by injecting TB antigens intradermally. A delayed-type hypersensitivity response, dependent on the presence of sensitized T cells, is seen in those infected with M. tuberculosis. This does not distinguish latent infection from active TB.

Pathogen-associated molecular pattern

A small molecular motif that is conserved across microbial species and engages innate immune receptors, in particular TLRs. Examples include lipopolysaccharide, peptidoglycan and flagellin.

Natural killer cell

A lymphocyte that does not express the T cell receptor or B cell receptor and that confers innate immunity.

T helper 2 cell

A type of activated T helper cell that participates in phagocytosis-independent responses and downregulates pro-inflammatory responses that are induced by T helper 1 cells. T helper 2 cells secrete IL-4, IL-5 and IL-6.

Regulatory T cell

A CD4+ T cell that naturally expresses high levels of CD25 (the IL-2 receptor subunit-α) and the transcription factor forkhead box P3 (FOXP3) and that has suppressive regulatory activity towards effector T cells and other immune cells.

Pyogenic bacterium

A pus-forming bacterium that is associated with exudative inflammation and neutrophil recruitment.

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Harding, C., Boom, W. Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Toll-like receptors. Nat Rev Microbiol 8, 296–307 (2010). https://doi.org/10.1038/nrmicro2321

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