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Tolerance: an overview and perspectives

Nature Reviews Nephrology volume 6, pages 569–576 (2010)Cite this article

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Abstract

Self tolerance is dependent on mechanisms that operate on T cells and B cells from the earliest stages, that is, from when they first express anti-self-receptors in the primary lymphoid organs of the thymus and bone marrow, all the way through to when they engage with self antigens in the peripheral immune system and within tissues themselves. This continuum of checkpoints and fail-safes ensures that the risk of developing harmful autoimmune diseases remains very small. Certain tissues have a degree of privilege that allows them to mute the immune response against them by mechanisms that are also well represented in cancers. An understanding of the underlying mechanisms of self tolerance is hoped to spawn a new range of therapeutics designed to both reprogram the immune system to avoid long-term intense immunosuppression, and to override the immune system to achieve more effective immunity against cancers and persistent viral infections.

Key Points

  • The immune system is organized so that it is free to react to dangerous microbes while avoiding reactions to self

  • Self tolerance in lymphocytes is organized so that many self-reactive lymphocytes abort soon after they acquire their receptors for antigen

  • Such purging cannot guarantee that self-reactivity will not occur, and other fail-safes operate at numerous checkpoints in the immune response

  • T-regulatory cells and agents that prevent licensing of antigen-presenting dendritic cells are the most amenable to therapeutic exploitation

  • Tissues can adapt to protect themselves against immune attack and can interact with regulatory cells of the innate and adaptive immune systems to create microenvironments that are protected from immune damage

  • Therapeutic exploitation of tolerance mechanisms is constrained by a number of commercial and regulatory issues, so that only part of what we know can ever become drug-worthy

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Figure 1: Inter-T-cell cooperation.
Figure 2: Decommissioning of dendritic cells is a mechanism by which TREG cells are thought to prevent cooperation and T-cell activation.
Figure 3: Factors that shape the engagement of T cells for immunity or tolerance.
Figure 4: Mechanisms by which TREG cells might interact with tissues to ensure their protection against immune damage.

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Change history

  • 03 September 2010

    In the version of this article initially published online, there was a mistake under the section T-regulatory cells. The errors have been corrected in all electronic versions of the text.

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Waldmann, H. Tolerance: an overview and perspectives. Nat Rev Nephrol 6, 569–576 (2010). https://doi.org/10.1038/nrneph.2010.108

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