Immunological Tolerance: Mechanisms

Moncef Zouali, Inserm & University Paris Diderot, Sorbonne Paris Cité, France

Published online: July 2014

DOI: 10.1002/9780470015902.a0000950.pub3

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.
close

References

Abbas AK, Benoist C, Bluestone JA et al. (2013) Regulatory T cells: recommendations to simplify the nomenclature. Nature Immunology 14(4): 307–308.

Allam JP and Novak N (2011) Local immunological mechanisms of sublingual immunotherapy. Current Opinion in Allergy and Clinical Immunology 11(6): 571–578.

Anderson G, Lane PJ and Jenkinson EJ (2007) Generating intrathymic microenvironments to establish T‐cell tolerance. Nature Reviews Immunology 7(12): 954–963.

Anolik JH, Barnard J, Owen T et al. (2007) Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy. Arthritis and Rheumatism 56(9): 3044–3056.

Barnes MJ and Powrie F (2009) Regulatory T cells reinforce intestinal homeostasis. Immunity 31(3): 401–411.

Billingham RE, Brent L and Medawar PB (1953) Actively acquired tolerance to foreign cells. Nature 172: 603–606.

Bloom B, Salgame P and Diamond B (1992) Revisiting and revising suppressor T cells. Immunology Today 13: 131–136.

Burnet M (1959) The Clonal Selection Theory of Acquired Immunity. Nashville, TN: Vanderbilt University Press.

Campbell DJ and Ziegler SF (2007) FOXP3 modifies the phenotypic and functional properties of regulatory T cells. Nature Reviews Immunology 7(4): 305–310.

Carosella ED, Gregori S and LeMaoult J (2011) The tolerogenic interplay(s) among HLA‐G, myeloid APCs, and regulatory cells. Blood 118(25): 6499–6505.

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.

Chase M (1946) Inhibition of experimental drug allergy by prior feeding of the sensitizing agent. Proceedings of the Society for Experimental Biology and Medicine 61: 257–259.

Chaudhry A, Rudra D, Treuting P et al. (2009) CD4+ regulatory T cells control TH17 responses in a Stat3‐dependent manner. Science 326(5955): 986–991.

Chen C, Nagy Z, Radic MZ et al. (1995) The site and stage of anti‐DNA B‐cell deletion. Nature 373(6511): 252–255.

DiLillo DJ, Matsushita T and Tedder TF (2010) B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer. Annals of the New York Academy of Sciences 1183: 38–57.

Duddy M, Niino M, Adatia F et al. (2007) Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. Journal of Immunology 178(10): 6092–6099.

Fridman WH, Mlecnik B, Bindea G, Pages F and Galon J (2011) Immunosurveillance in human non‐viral cancers. Current Opinion in Immunology 23(2): 272–278.

Gay D, Saunders T, Camper S and Weigert M (1993) Receptor editing: an approach by autoreactive B cells to escape tolerance. Journal of Experimental Medicine 177(4): 999–1008.

Glocker EO, Kotlarz D, Boztug K et al. (2009) Inflammatory bowel disease and mutations affecting the interleukin‐10 receptor. New England Journal of Medicine 361(21): 2033–2045.

Goodnow CC, Crosbie J, Adelstein S et al. (1988) Altered immunoglobulin expression and functional silencing of self‐reactive B lymphocytes in transgenic mice. Nature 334(6184): 676–682.

Griffith TS and Ferguson TA (2011) Cell death in the maintenance and abrogation of tolerance: the five Ws of dying cells. Immunity 35(4): 456–466.

Healy JI, Dolmetsch RE, Timmerman LA et al. (1997) Different nuclear signals are activated by the B cell receptor during positive versus negative signaling. Immunity 6(4): 419–428.

Hikada M and Zouali M (2010) Multistoried roles for B lymphocytes in autoimmunity. Nature Immunology 11(12): 1065–1068.

Hoehlig K, Shen P, Lampropoulou V et al. (2012) Activation of CD4(+) Foxp3(+) regulatory T cells proceeds normally in the absence of B cells during EAE. European Journal of Immunology 42(5): 1164–1173.

Huehn J, Polansky JK and Hamann A (2009) Epigenetic control of FOXP3 expression: the key to a stable regulatory T‐cell lineage? Nature Reviews Immunology 9(2): 83–89.

Iwata Y, Matsushita T, Horikawa M et al. (2011) Characterization of a rare IL‐10‐competent B‐cell subset in humans that parallels mouse regulatory B10 cells. Blood 117(2): 530–541.

Jerne N (1984) Idiotypic networks and other preconceived ideas. Immunological Reviews 79: 5–24.

Kamada N and Nunez G (2013) Role of the gut microbiota in the development and function of lymphoid cells. Journal of Immunology 190(4): 1389–1395.

Koch MA, Tucker‐Heard G, Perdue NR et al. (2009) The transcription factor T‐bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nature Immunology 10(6): 595–602.

Li L, Iwamoto Y, Berezovskaya A and Boussiotis VA (2006) A pathway regulated by cell cycle inhibitor p27Kip1 and checkpoint inhibitor Smad3 is involved in the induction of T cell tolerance. Nature Immunology 7(11): 1157–1165.

Lynch RJ and Platt JL (2009) Escaping from rejection. Transplantation 88(11): 1233–1236.

Matsushita T, Horikawa M, Iwata Y and Tedder TF (2010) Regulatory B cells (B10 cells) and regulatory T cells have independent roles in controlling experimental autoimmune encephalomyelitis initiation and late‐phase immunopathogenesis. Journal of Immunology 185(4): 2240–2252.

Matzinger P (2007) Friendly and dangerous signals: is the tissue in control? Nature Immunology 8(1): 11–13.

Mauri C and Bosma A (2012) Immune regulatory function of B cells. Annual Reviews of Immunology 30: 221–241.

Mills KH (2012) TLR‐dependent T cell activation in autoimmunity. Nature Reviews Immunology 11(12): 807–822.

Mosmann TR, Cherwinski H, Bond MW, Giedlin MA and Coffman RL (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. Journal of Immunology 136: 2348–2357.

Nemazee DA and Bürki K (1989) Clonal deletion of B lymphocytes in a transgenic mouse bearing anti‐MHC class I antibody genes. Nature 337: 562–566.

Nossal GJ and Pike BL (1980) Clonal anergy: persistence in tolerant mice of antigen‐binding B lymphocytes incapable of responding to antigen or mitogen. Proceedings of the National Academy of Sciences of the USA 77: 1602–1606.

Olenchock BA, Guo R, Carpenter JH et al. (2006) Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nature Immunology 7(11): 1174–1181.

Owen RD (1945) Immunogenetic consequences of vascular anastomoses between bovine twins. Science 102: 400–401.

Radic MZ and Zouali M (1996) Receptor editing, immune diversification, and self‐tolerance. Immunity 5(6): 505–511.

Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic self‐tolerance. Cell 101(5): 455–458.

Shen P, Roch T, Lampropoulou V et al. (2014) IL‐35‐producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507(7492): 366–370.

Shevach EM (2009) Mechanisms of foxp3+ T regulatory cell‐mediated suppression. Immunity 30(5): 636–645.

Spitaler M, Emslie E, Wood CD and Cantrell D (2006) Diacylglycerol and protein kinase D localization during T lymphocyte activation. Immunity 24(5): 535–546.

Tiegs SL, Russell DM and Nemazee D (1993) Receptor editing in self‐reactive bone marrow B cells. Journal of Experimental Medicine 177(4): 1009–1020.

Van Parijs L and Abbas A (1998) Homeostasis and self‐tolerance in the immune system: turning lymphocyte off. Science 280: 243–248.

Weiner HL, da Cunha AP, Quintana F and Wu H (2011) Oral tolerance. Immunological Reviews 241(1): 241–259.

Yoshizaki A, Miyagaki T, DiLillo DJ et al. (2012) Regulatory B cells control T‐cell autoimmunity through IL‐21‐dependent cognate interactions. Nature 491(7423): 264–268.

Zha Y, Marks R, Ho AW et al. (2006) T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase‐alpha. Nature Immunology 7(11): 1166–1173.

Zheng Y, Chaudhry A, Kas A et al. (2009) Regulatory T‐cell suppressor program co‐opts transcription factor IRF4 to control T(H)2 responses. Nature 458(7236): 351–356.

Zouali M (ed.) (2005) Molecular Autoimmunity. New York, NY: Springer.

Zouali M (2008) Receptor editing and receptor revision in rheumatic autoimmune diseases. Trends in Immunology 29(3): 103–109.

Zouali M, Isenberg D and Morrow JWW (1996) Idiotype network manipulation for autoimmune diseases: where are we going. Autoimmunity 24: 55–63.

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.

Griffith TS and Ferguson TA (2011) Cell death in the maintenance and abrogation of tolerance: the five Ws of dying cells. Immunity 35(4): 456–466.

Healy J and Goodnow C (1998) Positive versus negative signaling by lymphocyte antigen receptors. Annual Review of Immunology 16: 645–670.

Kappler JW, Roehm N and Marrack P (1987) T cell tolerance by clonal elimination in the thymus. Cell 49: 273–280.

Paul WE (2012) Fundamental Immunology, 7th edn. New York, NY: Lippincott Williams & Wilkins.

Zouali M (ed.) (2009) The Epigenetics of Autoimmune Diseases. Hoboken, New Jersey, USA: Wiley‐Blackwell. (an imprint of John Wiley & Sons Ltd).

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.

Related Sub-Topics:

Acquired (Adaptive) Immunity | Diagnostics, Therapeutics and Methods | Transplantation | Antigens | Autoimmunity
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

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