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  • Review Article
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Primer: mechanisms of immunologic tolerance

Nature Clinical Practice Rheumatology volume 2, pages 44–52 (2006)Cite this article

Abstract

Successful adaptive immunity against a broad range of pathogens depends on the diversity of randomly generated T-lymphocyte and B-lymphocyte receptors. A subset of these receptors will be self-reactive and must be regulated to prevent autoimmunity. The process of immunologic tolerance addresses this problem by either purging autoreactive receptors from the system or tuning down their reactivity sufficiently to prevent disease. Immature lymphocytes generate a novel receptor during development in the thymus or bone marrow. Engagement of self antigens by these nascent receptors leads to their purging, either by the apoptotic death of the lymphocyte or by the initiation of receptor editing, a process in which the autoreactive receptor is replaced. If the lymphocytes mature further, the activation threshold of autoreactive cells can be tuned by the co-expression of inhibitory receptors or negative signaling molecules, allowing the persistence of the receptor without an increased risk of autoimmunity. T-cell and B-cell receptors that escape these checkpoints can still be regulated in the peripheral immune system by both purging and tuning mechanisms. A separate set of mechanisms, mediated by various regulatory cells, also operates to tune peripheral receptors in a cell-extrinsic fashion. The combined action of these processes ensures that the organism does not suffer autoimmune pathology, even if autoreactive receptors are generated and maintained in the immune system.

Key Points

  • Immunologic tolerance operates to prevent randomly generated self-reactive T-cell and B-cell receptors from triggering autoimmunity

  • Purging and tuning of the autoreactive receptors are the two strategies used to maintain immunologic tolerance

  • Purging is accomplished by the induction of apoptosis in the lymphocyte expressing the autoreactive receptor or by the process of receptor editing, in which the autoreactive receptor is replaced with a newly rearranged one

  • Tuning can be cell-intrinsic (adaptation) or cell-extrinsic (regulatory) and allows the self-reactive receptor to persist in the periphery without initiating autoimmunity

  • Adaptation is achieved by expression of inhibitory receptors or negative-regulatory signaling molecules in the lymphocyte, which increases its threshold for activation by the autoreactive receptor

  • Cell-extrinsic tuning is mediated by regulatory cells, including CD4+ regulatory T cells, natural killer T cells, and antigen-presenting cells, that might prevent activation of the self-reactive lymphocyte or modulate its differentiation process

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Figure 1: Mechanisms that purge or tune autoreactive receptors in the immune system.
Figure 2: Intracellular cascades involved in purging autoreactive receptors.
Figure 3: Cell-intrinsic tuning of autoreactive receptors.

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Acknowledgements

This work was supported by the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases at the National Institutes of Health, Bethesda, MD, USA.

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Authors and Affiliations

  1. Laboratory Chief in the Laboratory of Cellular and Molecular Immunology at the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, Bethesda, MD, USA

    Nevil J Singh

  2. Research Fellow in the Laboratory of Cellular and Molecular Immunology at the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, Bethesda, MD, USA

    Ronald H Schwartz

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Correspondence to Ronald H Schwartz.

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Singh, N., Schwartz, R. Primer: mechanisms of immunologic tolerance. Nat Rev Rheumatol 2, 44–52 (2006). https://doi.org/10.1038/ncprheum0049

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