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Regulation of Immunity to Tuberculosis

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  • Authors: Susanna Brighenti1, Diane J. Ordway2
  • Editors: William R. Jacobs Jr.3, Helen McShane4, Valerie Mizrahi5, Ian M. Orme6
    Affiliations: 1: Center for Infectious Medicine (CIM), F59, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; 2: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523; 3: Howard Hughes Medical Institute, Albert Einstein School of Medicine, Bronx, NY 10461; 4: University of Oxford, Oxford OX3 7DQ, United Kingdom; 5: University of Cape Town, Rondebosch 7701, South Africa; 6: Colorado State University, Fort Collins, CO 80523
  • Source: microbiolspec December 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.TBTB2-0006-2016
  • Received 06 January 2016 Accepted 29 February 2016 Published 09 December 2016
  • Diane J. Ordway, [email protected]
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  • Abstract:

    Immunity against requires a balance between adaptive immune responses to constrain bacterial replication and the prevention of potentially damaging immune activation. Regulatory T (Treg) cells express the transcription factor Foxp3+ and constitute an essential counterbalance of inflammatory Th1 responses and are required to maintain immune homeostasis. The first reports describing the presence of Foxp3-expressing CD4+ Treg cells in tuberculosis (TB) emerged in 2006. Different Treg cell subsets, most likely specialized for different tissues and microenvironments, have been shown to expand in both human TB and animal models of TB. Recently, additional functional roles for Treg cells have been demonstrated during different stages and spectrums of TB disease. Foxp3+ regulatory cells can quickly expand during early infection and impede the onset of cellular immunity and persist during chronic TB infection. Increased frequencies of Treg cells have been associated with a detrimental outcome of active TB, and may be dependent on the strain, animal model, local environment, and the stage of infection. Some investigations also suggest that Treg cells are required together with effector T cell responses to obtain reduced pathology and sterilizing immunity. In this review, we will first provide an overview of the regulatory cells and mechanisms that control immune homeostasis. Then, we will review what is known about the phenotype and function of Treg cells from studies in human TB and experimental animal models of TB. We will discuss the potential role of Treg cells in the progression of TB disease and the relevance of this knowledge for future efforts to prevent, modulate, and treat TB.

  • Citation: Brighenti S, Ordway D. 2016. Regulation of Immunity to Tuberculosis. Microbiol Spectrum 4(6):TBTB2-0006-2016. doi:10.1128/microbiolspec.TBTB2-0006-2016.


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Immunity against requires a balance between adaptive immune responses to constrain bacterial replication and the prevention of potentially damaging immune activation. Regulatory T (Treg) cells express the transcription factor Foxp3+ and constitute an essential counterbalance of inflammatory Th1 responses and are required to maintain immune homeostasis. The first reports describing the presence of Foxp3-expressing CD4+ Treg cells in tuberculosis (TB) emerged in 2006. Different Treg cell subsets, most likely specialized for different tissues and microenvironments, have been shown to expand in both human TB and animal models of TB. Recently, additional functional roles for Treg cells have been demonstrated during different stages and spectrums of TB disease. Foxp3+ regulatory cells can quickly expand during early infection and impede the onset of cellular immunity and persist during chronic TB infection. Increased frequencies of Treg cells have been associated with a detrimental outcome of active TB, and may be dependent on the strain, animal model, local environment, and the stage of infection. Some investigations also suggest that Treg cells are required together with effector T cell responses to obtain reduced pathology and sterilizing immunity. In this review, we will first provide an overview of the regulatory cells and mechanisms that control immune homeostasis. Then, we will review what is known about the phenotype and function of Treg cells from studies in human TB and experimental animal models of TB. We will discuss the potential role of Treg cells in the progression of TB disease and the relevance of this knowledge for future efforts to prevent, modulate, and treat TB.

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Regulatory T cell suppression of antigen-presenting cells (APCs). CTLA-4 on the surface of Treg cells can prevent or depress the upregulation of CD80 and CD86, the major costimulatory molecules on APC. LAG-3 on Treg cells can interact with MHC class II on APCs, by binding of LAG-3 to MHC class II molecules on immature DCs, causing an inhibitory signal that suppresses DC maturation and immaturity. Tissue destruction results in extracellular ATP that functions as an indicator and exerts inflammatory effects on DCs. Catalytic inactivation of extracellular ATP by CD39 represents an anti-inflammatory mechanism that may be used by Treg cells to prevent the deleterious effects of ATP on antigen-presenting cell function. In contrast, Nrp-1 (neuropilin) promotes extended interactions between Treg cells and immature DCs and limits access of the effector cells to APCs.

Source: microbiolspec December 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.TBTB2-0006-2016
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A combination of host immune factors and strain virulence can result in a distinctive host immunophenotype over time, resulting in multiple outcomes. During infection too little Treg activity can lead to a greater Th1 immune response, resulting in tissue damage and bacterial growth. A balance of both Th1 and Treg immunity can result in proper antibacterial immunity, leading to reduced TB growth. Excessive Treg activity results in a counterregulatory Treg response that ultimately impairs host immunity against the tubercle bacillus, allowing disease progression.

Source: microbiolspec December 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.TBTB2-0006-2016
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Model of proposed regulatory T cell suppression in mice BCG vaccinated and exposed to clinical and clinical alone. The initial BCG vaccination results in bacterial lymph node persistence in the animal TB model that leads to the presence of Treg and Th17 cells. Upon a subsequent infection with Th1 and Th17 cells expand at a high rate, causing GR1+ influx and pulmonary tissue damage. In an attempt to limit this damage Tregs expand with Th1 immunity and produce IL-10 and CTLA4 binds to CD80/CD86 costimulatory molecules to limit effector T cell expansion. The abundance of Th17 cells can also have a negative regulatory feedback on Th1 effector cells. infection in mice results in expansion of Th1 IFN-γ effector cells capable of limiting further expansion of Th17 cells producing IL-17 induction of GR1+ cells and pulmonary pathology. Treg cells will expand with the Th1 effector immunity limiting Th17 cells through IL-2 consumption with CD25 or IL-10 production.

Source: microbiolspec December 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.TBTB2-0006-2016
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Impacts of Foxp3+ on host defense against

Source: microbiolspec December 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.TBTB2-0006-2016

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