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  • Review Article
  • Published:

Regulatory T cells and infection: a dangerous necessity

Nature Reviews Immunology volume 7, pages 875–888 (2007)Cite this article

Key Points

  • Several types of regulatory T cell have been described on the basis of their origin, generation and mechanism of action, with two main subsets identified: natural regulatory T (TReg) cells, which mainly develop in the thymus and regulate self-reactive T cells in the periphery, and inducible regulatory T cells, which develop in the periphery from conventional CD4+ T cells.

  • In some infections, natural TReg cells mediate a compromise between the host and the pathogen by favouring pathogen expansion and persistence while limiting immunopathology.

  • The nature of the antigens recognized by natural TReg cells during infection is not well understood. During the onset of acute infection, natural TReg cells could recognize self antigens that are released by tissue damage; however, during chronic infection, evidence suggests that natural TReg cells recognize microbial antigens.

  • During various infections, interleukin-10 (IL-10)-producing T regulatory 1 (TR1) cells develop from conventional T cells after encounter with certain signals, such as exposure to deactivated or immature antigen-presenting cells, repeated exposure to antigen, exposure to microbial products or IL-10 itself.

  • CD4+ T cells that produce both interferon-γ (IFNγ) and IL-10 also can emerge during certain experimental infections and have an important role in the control of T helper 1 (TH1)-cell-mediated immunopathology.

  • Recent evidence supports the idea that infection-induced regulatory T cells can have a major role in the outcome of secondary infections, as well as in autoimmune or allergic responses.

  • Microorganisms themselves can promote the emergence, survival, recruitment or function of TReg cells to favour their own survival.

  • In some circumstances, the regulation exerted by regulatory T cells is excessive and therefore prevents the establishment of protective immune responses, whereas in other circumstances, this control is not sufficient to prevent immunopathology. At both extremes, manipulation of regulatory T cells could offer therapeutic potential.

Abstract

Surviving a given infection requires the generation of a controlled immune response. Failure to establish or restore homeostatic conditions during or following the onset of an infection can lead to tissue damage. Investigation of the immunoregulatory network that arises in response to the infectious process or that is induced by the pathogen itself should provide insight into therapeutic approaches for the control of infection and any subsequent immunopathology. In this Review, I discuss current hypotheses and points of polemic associated with the origin, mode of action and antigen specificity of the various populations of regulatory T cells that arise during infection.

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Figure 1: Regulatory T cells during infection.
Figure 2: The nature of regulatory T cells involved and the mechanism of suppression depend on the strength and stage of the pathological process.
Figure 3: Origin and specificity of natural regulatory T cells during infections.
Figure 4: Positive and negative roles of regulatory T cells during infection.
Figure 5: Potential strategies used by pathogens to promote regulatory T-cell induction and functions.

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Acknowledgements

This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. I apologize to those authors whose work I could not cite because of space limitations.

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  1. Mucosal Immunology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 4 Center Drive, Room 4/126, Bethesda, 20892, Maryland, USA

    Yasmine Belkaid

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Glossary

Colitis

An inflammatory disease of the colon. In humans, colitis is most commonly classified as ulcerative colitis or Crohn's disease, two inflammatory bowel diseases that have unknown aetiology. Various hereditary and induced mouse models of human colitis have been developed.

Filarial diseases

Diseases such as human river blindness and elephantiasis that are caused by filarial nematodes.

Thymic involution

The age-dependent decrease of thymic epithelial volume, which results in decreased production of T cells.

Bystander suppression

Inhibition of effector T-cell function by regulatory T cells of different antigen specificity.

Experimental autoimmune encephalomyelitis

(EAE). An experimental model of the human disease multiple sclerosis. EAE is an autoimmune disease mediated by CD4+ T helper 1 (TH1) cells and interleukin-17-producing TH17 cells reactive to components of the myelin sheath that infiltrate the nervous parenchyma, release pro-inflammatory cytokines and chemokines, promote leukocyte infiltration and contribute to demyelination.

Non-obese diabetic mice

(NOD mice). A strain of mice that normally develops idiopathic autoimmune diabetes that very closely resembles type 1 diabetes in humans. The target antigen(s) that is recognized by the pathogenic CD4+ T cells that initiate disease is expressed by pancreatic islet cells, but its identity has remained elusive.

Probiotic

Viable bacteria used therapeutically or prophylactically for colonization of the intestine for the purpose of modifying the intestinal microflora in ways presumed to be beneficial to the host.

B16 melanoma

A widely used experimental mouse melanoma. B16 melanoma is poorly immunogenic and therefore is difficult for the immune system to eliminate. Largely because of this, it makes a good model for testing cancer immunotherapies.

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Belkaid, Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol 7, 875–888 (2007). https://doi.org/10.1038/nri2189

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