Immunological Tolerance: Mechanisms

Abstract

Immunological tolerance refers to a reduction or complete inhibition of the ability of an individual to mount a specific immune response upon immunisation. Several mechanisms are involved in induction and maintenance of tolerance, including clonal deletion, clonal anergy, receptor editing, receptor down‐modulation and lymphocyte sequestration. The number of antigen presenting cells, the number and activity of regulatory T cells and regulatory B cells, the nature and amount of antigenic peptides generated and the presence of co‐stimulatory signals in a particular tissue are also important. Depending on the site and the level of antigen expression, different states of peripheral B‐cell and T‐cell tolerance can be reached. In certain situations, they could act in an additive manner. In humans, induction of immunological tolerance is an important issue in both transplantation biology and autoimmune diseases, and present research aims at designing novel strategies to induce specific tolerance.

Key Concepts:

  • Tolerance induction is easier in animals with an immature immune system or with a mature immune system that has been compromised by irradiation, drugs or thoracic drug drainage.

  • In general, when a given antigen is used over a wide range of concentrations, intermediate doses induce immunity, and low and high doses induce tolerance.

  • The introduction route is a key variable in tolerance induction, particularly in adult animals, presumably by determining the accessibility of the antigen to professional antigen presenting cells.

  • The tolerant state is not absolute and tolerance is rarely complete. With time, it gradually wanes and eventually disappears, but it can be deliberately terminated by several means.

  • Persistence of the tolerogen in the periphery and its accessibility to the immune system are generally required to maintain tolerance, which continuously inactivates newly emerging T and B cells that develop in lymphoid organs.

  • T lymphocytes specific for self‐peptides bound to major histocompatibility complex peptides are eliminated by clonal deletion, a process known as negative selection. Similarly, self‐reactive B cells are purged from the functional repertoire during the transition from the pre‐B to mature B‐cell stage in the bone marrow.

  • Anergy is a functionally silent state induced in B cells and T cells, allowing them to persist functionally inactivated in tolerant animals.

  • Receptor editing is a form of receptor processing that markedly alters the variable region genes expressed by B cells and, consequently, changes the specificity of the surface immunoglobulin and maintains B‐cell tolerance to self.

  • Two functional lymphocyte subsets, called regulatory T cells and regulatory B cells, have recently been found to contribute to the maintenance of the fine equilibrium required for immune tolerance.

  • In humans, induction of immunological tolerance in the adult is an important issue in both transplantation biology and autoimmune diseases, and present research aims at designing novel strategies to induce specific tolerance.

Keywords: transplantation; autoimmunity; immune privilege; deletion; anergy; receptor editing; regulatory T cells; regulatory B cells

Figure 1.

High‐ and low‐dose tolerance. When a given antigen is used over a wide range of concentrations, intermediate doses induce immunity, and low and high doses induce tolerance.

Figure 2.

Clonal deletion. The fate of B lymphocytes is governed by the specificity of their receptors. Encounter of a self‐reactive B cell with an autoantigen leads to its physical elimination by apoptotic death. By contrast, a nonautoreactive B cell will persist in the primary repertoire and can engage in an immune response against a potential threat.

Figure 3.

Clonal anergy. In this tolerance mechanism, a self‐reactive B cell encountering its target autoantigen will undergo a state of functional silencing, but will persist in the immune repertoire. Upon receiving additional B cell engagement in the presence of T lymphocyte help, the anergic B cell can regain a functional state and become a member of the lymphocyte repertoire.

Figure 4.

Receptor editing. Upon encounter with a self‐antigen, the autoreactive B cell initiates a series of successive Ig gene rearrangements that lead to expression of a new Ig cell surface receptor. As a result, the B cell will extinguish its autoreactivity, acquire a new specificity and persist in the immune repertoire.

Figure 5.

Mechanisms of receptor editing at the kappa‐chain and heavy (H)‐chain Ig loci. (a) Revision of a primary Vκ‐Jκ rearrangement. Vκ genes rearrange by inversion or deletion. Once a primary rearrangement has been obtained, a secondary rearrangement may also use either deletion or inversion, depending on the orientation of the Vκ involved. Shown are both types of secondary rearrangements that may be used by B cells to revise their B‐cell receptor and acquire a new specificity. The two different recombination signal sequences are indicated by numbers. For simplicity, both secondary rearrangements are shown to involve the same downstream Jκ, but different Vκ genes. Arrows indicate each of the expressed Vκ‐Jκ rearrangements. Reproduced with permission from Radic and Zouali () © Elsevier Ltd. (b) Variable gene replacement at the H‐chain Ig locus. Secondary rearrangement of a VH gene to edit a primary VH‐D‐JH joint occurs by deletion. The conserved heptamer‐nonamer, that is embedded within the 3′ end of most VH germline genes, and the standard flanking recombination signal sequences are shown. The expressed VH‐D‐JH joints are indicated by arrows. During the secondary rearrangement, a variable amount of the original VH‐D junction may remain and N nucleotides may be added to the new junction. Reproduced with permission from Radic and Zouali () © Elsevier Ltd.

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Further Reading

Chappert P and Schwartz RH (2010) Induction of T cell anergy: integration of environmental cues and infectious tolerance. Current Opinion in Immunology 22(5): 552–559.

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Zouali M (2013) The epigenetic landscape of B lymphocyte tolerance to self. FEBS Letters 587(13): 2067–2073.

Zouali M (2014) Tweaking the B lymphocyte compartment in autoimmune diseases. Nature Immunology 15(3): 209–212.

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Zouali, Moncef(Jul 2014) Immunological Tolerance: Mechanisms. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000950.pub3]