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  • Review Article
  • Published:

The enemy within: keeping self-reactive T cells at bay in the periphery

Nature Reviews Immunology volume 2, pages 11–19 (2002)Cite this article

Key Points

  • Thymic deletion clearly fails to eliminate all self-reactive T cells; therefore, peripheral tolerance mechanisms are required to prevent autoimmune disease.

  • Peripheral tolerance mechanisms can be subdivided into those that act directly on the responding T cell (T-cell intrinsic) and those with an indirect effect (T-cell extrinsic).

  • T-cell intrinsic mechanisms of tolerance to self-antigens include ignorance, anergy, phenotypic skewing and activation induced cell death.

  • T-cell extrinsic mechanisms of self-tolerance have received much recent press, and include control of the phenotype of the dendritic cell presenting self-antigen, and the involvement of regulatory T cells.

  • How infections might interfere with pathways of tolerance and permit induction of autoimmune disorders is an ongoing area of research.

Abstract

The remarkable capacity of the mammalian immune system to coordinate deadly attacks against numerous invading pathogens, yet turn a blind eye to self-tissues continues to fascinate immunologists. It has been clear for some time that immune cells capable of recognizing self-proteins exist in normal individuals without seemingly causing harm. The 'peripheral tolerance' mechanisms that keep these cells in check are the focus of intense research, not least because defects in these pathways might cause autoimmune diseases. In this review, new developments in our understanding of peripheral tolerance are discussed.

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Figure 1: Pathways to tolerance.
Figure 2: T-cell-intrinsic mechanisms of peripheral tolerance.
Figure 3: Role of dendritic cells in the choice between immunity and tolerance.
Figure 4: Links between infection and autoimmunity.

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Acknowledgements

We are grateful to M. Krummel, L. Kane and A. Chodos for helpful comments on the manuscript.

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Authors and Affiliations

  1. Department of Pathology, University of California San Francisco, San Francisco, 94143, California, USA

    Lucy S.K. Walker & Abul K. Abbas

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  1. Lucy S.K. Walker
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  2. Abul K. Abbas
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Correspondence to Lucy S.K. Walker.

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DATABASES

LocusLink

CD2

CD25

CD28

CD58

CD80

CD86

CD95

CD178

CTLA-4

CXCL13

CXCR5

FLIP

GAD

IL-2

IL-2 receptor

IL-10

PD-1

Pten

Stat5

TGF-β

Tlr4

OMIM

autoimmune lymphoproliferative syndrome

multiple sclerosis

FURTHER INFORMATION

Abul Abbas's lab

autoimmune disease

dendritic cells (T lymphocyte stimulating)

immunological tolerance: mechanisms

Glossary

PERIPHERAL TOLERANCE

Control of self-reactive T cells in the periphery.

CENTRAL TOLERANCE

Deletion of self-reactive T cells in the thymus.

ANERGY

State of unresponsiveness to antigen.

ACTIVATION-INDUCED CELL DEATH

(AICD). Pathway of T-cell suicide often involving upregulation of Fas ligand that binds to the death receptor Fas.

SUPERANTIGEN

Protein that binds to and activates all T cells that express a particular set of Vβ T-cell receptor genes.

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Walker, L., Abbas, A. The enemy within: keeping self-reactive T cells at bay in the periphery. Nat Rev Immunol 2, 11–19 (2002). https://doi.org/10.1038/nri701

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