self tolerance


Summary: The normal lack of the ability to produce an immunological response to autologous (self) antigens. A breakdown of self tolerance leads to autoimmune diseases. The ability to recognize the difference between self and non-self is the prime function of the immune system.

Top Publications

  1. Gray D, Kupresanin F, Berzins S, Herold M, O Reilly L, Bouillet P, et al. The BH3-only proteins Bim and Puma cooperate to impose deletional tolerance of organ-specific antigens. Immunity. 2012;37:451-62 pubmed publisher
    ..Our data show that Puma cooperates with Bim to impose a thymic-deletion checkpoint to peripheral self-antigens and cement the notion that defects in apoptosis alone are sufficient to cause autoimmune disease. ..
  2. Zhu B, Symonds A, Martin J, Kioussis D, Wraith D, Li S, et al. Early growth response gene 2 (Egr-2) controls the self-tolerance of T cells and prevents the development of lupuslike autoimmune disease. J Exp Med. 2008;205:2295-307 pubmed publisher
    ..These results demonstrate that Egr-2 is an intrinsic regulator of effector T cells and controls the expansion of self-reactive T cells and development of autoimmune disease. ..
  3. Hadeiba H, Sato T, Habtezion A, Oderup C, Pan J, Butcher E. CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nat Immunol. 2008;9:1253-60 pubmed publisher
    ..Our results identify a highly immunosuppressive population of pDCs present in lymphoid tissues. ..
  4. Peterson P, Org T, Rebane A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat Rev Immunol. 2008;8:948-57 pubmed publisher
    The negative selection of T cells in the thymus is necessary for the maintenance of self tolerance. Medullary thymic epithelial cells have a key function in this process as they express a large number of tissue-specific self antigens that ..
  5. Yano M, Kuroda N, Han H, Meguro Horike M, Nishikawa Y, Kiyonari H, et al. Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance. J Exp Med. 2008;205:2827-38 pubmed publisher
    ..Our results suggest that Aire controls the differentiation program of mTECs, thereby organizing the global mTEC integrity that enables TRA expression from terminally differentiated mTECs in the thymic microenvironment. ..
  6. Yu J, Venstrom J, Liu X, Pring J, Hasan R, O Reilly R, et al. Breaking tolerance to self, circulating natural killer cells expressing inhibitory KIR for non-self HLA exhibit effector function after T cell-depleted allogeneic hematopoietic cell transplantation. Blood. 2009;113:3875-84 pubmed publisher
  7. Mamessier E, Sylvain A, Thibult M, Houvenaeghel G, Jacquemier J, Castellano R, et al. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J Clin Invest. 2011;121:3609-22 pubmed publisher
    ..This highlights the importance of developing future therapies able to restore NK cell cytotoxicity to limit/prevent tumor escape from antitumor immunity. ..
  8. Tykocinski L, Sinemus A, Rezavandy E, Weiland Y, Baddeley D, Cremer C, et al. Epigenetic regulation of promiscuous gene expression in thymic medullary epithelial cells. Proc Natl Acad Sci U S A. 2010;107:19426-31 pubmed publisher
    ..Transient gene expression could conceivably add to the local diversity of self-antigen display thus enhancing the efficacy of central tolerance. ..
  9. Venanzi E, Melamed R, Mathis D, Benoist C. The variable immunological self: genetic variation and nongenetic noise in Aire-regulated transcription. Proc Natl Acad Sci U S A. 2008;105:15860-5 pubmed publisher
    ..This variable self may be beneficial in preventing uniform holes in the T-cell repertoire in individuals of a species, but at the cost of variable susceptibility to autoimmunity. ..

More Information


  1. Burchill M, Yang J, Vang K, Moon J, Chu H, Lio C, et al. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity. 2008;28:112-21 pubmed publisher
    ..Our data support a two-step model of Treg cell differentiation in which TCR and CD28 signals induce cytokine responsiveness and STAT5-inducing cytokines then complete the program of Treg cell differentiation. ..
  2. Gardner J, DeVoss J, Friedman R, Wong D, Tan Y, Zhou X, et al. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science. 2008;321:843-7 pubmed publisher
    ..We propose that such a secondary network of self-antigen-expressing stromal cells may help reinforce immune tolerance by preventing the maturation of autoreactive T cells that escape thymic negative selection. ..
  3. Liu G, Gomes A, Fang L, Gao X, Hjelmstrom P. Decreased 4-1BB expression on CD4+CD25 high regulatory T cells in peripheral blood of patients with multiple sclerosis. Clin Exp Immunol. 2008;154:22-9 pubmed publisher
    ..The elevated s4-1BB levels may, at least in part, function as a self-regulatory attempt to inhibit antigen-driven proliferation of Tregs or their immunosuppressive activity. ..
  4. Joncker N, Raulet D. Regulation of NK cell responsiveness to achieve self-tolerance and maximal responses to diseased target cells. Immunol Rev. 2008;224:85-97 pubmed publisher
  5. Sakaguchi S. Regulatory T cells: history and perspective. Methods Mol Biol. 2011;707:3-17 pubmed publisher
    ..Treg cells are now within the scope of clinical use to treat immunological diseases and control physiological and pathological immune responses. ..
  6. Sola C, Andre P, Lemmers C, Fuseri N, Bonnafous C, Blery M, et al. Genetic and antibody-mediated reprogramming of natural killer cell missing-self recognition in vivo. Proc Natl Acad Sci U S A. 2009;106:12879-84 pubmed publisher
    ..Finally, the long-term infusion of anti-KIR mAb neither abolished NK cell education nor tumor cell recognition. Therefore, these results strongly support the use of inhibitory receptor blockade in cancer patients. ..
  7. Kasai M, Tanida I, Ueno T, Kominami E, Seki S, Ikeda T, et al. Autophagic compartments gain access to the MHC class II compartments in thymic epithelium. J Immunol. 2009;183:7278-85 pubmed publisher
    ..These results strongly suggest that the cytoplasmic self-Ags gain access to the H2-DM-positive compartments via the autophagic process in the thymus. ..
  8. Joncker N, Shifrin N, Delebecque F, Raulet D. Mature natural killer cells reset their responsiveness when exposed to an altered MHC environment. J Exp Med. 2010;207:2065-72 pubmed publisher
    ..These findings have important implications for how NK cell functions may be curtailed or enhanced in the context of disease. ..
  9. Mukhopadhyay S, Plüddemann A, Gordon S. Macrophage pattern recognition receptors in immunity, homeostasis and self tolerance. Adv Exp Med Biol. 2009;653:1-14 pubmed
    ..In the light of present knowledge ofmacrophage surface antigens, we discuss self versus nonself recognition, microbicidal effector functions and self tolerance in the innate immune system.
  10. Klein L, Hinterberger M, Wirnsberger G, Kyewski B. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol. 2009;9:833-44 pubmed publisher
    Understanding how thymic selection imparts self-peptide-MHC complex restriction and a high degree of self tolerance on the T cell repertoire requires a detailed description of the parameters that shape the MHC ligand repertoire of ..
  11. Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010;11:7-13 pubmed publisher
    Immunological self tolerance is maintained at least in part by regulatory T (T(reg)) cells that actively and dominantly control potentially hazardous self-reactive T cells in the periphery...
  12. Colombo M, Piconese S. Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nat Rev Cancer. 2007;7:880-7 pubmed
  13. Shlomchik M. Sites and stages of autoreactive B cell activation and regulation. Immunity. 2008;28:18-28 pubmed publisher
    ..Integrating classic work with recent insights, emphasis is placed on efforts to pinpoint the precursor cells for autoantibody-secreting cells and the unique stimuli and pathways by which they are activated. ..
  14. Ohnmacht C, Pullner A, King S, Drexler I, Meier S, Brocker T, et al. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J Exp Med. 2009;206:549-59 pubmed publisher
    ..This demonstrates that DCs play an essential role to protect against fatal autoimmunity under steady-state conditions. ..
  15. Kim H, Verbinnen B, Tang X, Lu L, Cantor H. Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature. 2010;467:328-32 pubmed publisher
    ..Here we delineate a CD8(+) regulatory T-cell lineage that is essential for the maintenance of self tolerance and prevention of murine autoimmune disease...
  16. Stritesky G, Jameson S, Hogquist K. Selection of self-reactive T cells in the thymus. Annu Rev Immunol. 2012;30:95-114 pubmed publisher
    ..We also outline molecular pathways unique to each lineage and consider possible commonalities to their development and survival...
  17. Coquerelle C, Moser M. Are dendritic cells central to regulatory T cell function?. Immunol Lett. 2008;119:12-6 pubmed publisher
    ..In this review, we summarize the observations supporting the hypothesis that DCs induce and maintain tolerance by a mechanism involving regulatory T cells. ..
  18. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775-87 pubmed publisher
    ..Recent research reveals the cellular and molecular basis of Treg development and function and implicates dysregulation of Tregs in immunological disease. ..
  19. Teague R, Greenberg P, Fowler C, Huang M, Tan X, Morimoto J, et al. Peripheral CD8+ T cell tolerance to self-proteins is regulated proximally at the T cell receptor. Immunity. 2008;28:662-74 pubmed publisher
  20. Lio C, Hsieh C. A two-step process for thymic regulatory T cell development. Immunity. 2008;28:100-11 pubmed publisher
  21. Vahlne G, Lindholm K, Meier A, Wickström S, Lakshmikanth T, Brennan F, et al. In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: maintained tolerance to normal cells even in the presence of IL-2. Eur J Immunol. 2010;40:813-23 pubmed publisher
    ..c. inoculation 3 days before start of treatment. Our results demonstrate that inhibitory receptor blockade does not result in attack on normal cells, despite potent reactivity against MHC class I-expressing tumors. ..
  22. Brodin P, Lakshmikanth T, Johansson S, Kärre K, Höglund P. The strength of inhibitory input during education quantitatively tunes the functional responsiveness of individual natural killer cells. Blood. 2009;113:2434-41 pubmed publisher
    ..Our data suggest that the capacity of an individual NK cell to respond to stimulation is quantitatively controlled by the extent of inhibitory signals that are received from MHC class I molecules during NK-cell education. ..
  23. Matsumoto M. Contrasting models for the roles of Aire in the differentiation program of epithelial cells in the thymic medulla. Eur J Immunol. 2011;41:12-7 pubmed publisher
    ..e. Aire does not play a neutral role in mTEC differentiation. This review discusses when and how Aire plays an important role in controlling the organization of mTECs required for the expression of self-antigen genes. ..
  24. Lei Y, Ripen A, Ishimaru N, Ohigashi I, Nagasawa T, Jeker L, et al. Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J Exp Med. 2011;208:383-94 pubmed publisher
    ..These results indicate that the XCL1-mediated medullary accumulation of tDCs contributes to nT reg cell development and is regulated by Aire. ..
  25. Meager A, Peterson P, Willcox N. Hypothetical review: thymic aberrations and type-I interferons; attempts to deduce autoimmunizing mechanisms from unexpected clues in monogenic and paraneoplastic syndromes. Clin Exp Immunol. 2008;154:141-51 pubmed publisher
    ..These ideas raise numerous questions that others may already have the materials to address...
  26. Giraud M, Yoshida H, Abramson J, Rahl P, Young R, Mathis D, et al. Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. Proc Natl Acad Sci U S A. 2012;109:535-40 pubmed publisher
    ..Thus, transcript mapping and ChIP-seq data indicate that Aire activates ectopic transcription not through specific recognition of PTA gene promoters but by releasing stalled polymerases. ..
  27. Aschenbrenner K, D Cruz L, Vollmann E, Hinterberger M, Emmerich J, Swee L, et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol. 2007;8:351-8 pubmed
    ..Thus, 'routing' of mTEC-derived self antigens may determine whether specific thymocytes are deleted or enter the regulatory T cell lineage. ..
  28. Raulet D. Missing self recognition and self tolerance of natural killer (NK) cells. Semin Immunol. 2006;18:145-50 pubmed
    ..can be modulated independently of inhibitory receptors specific for MHC molecules, and that such modulation may contribute to self tolerance. This review summarizes current understanding of NK cell recognition and self tolerance.
  29. Raulet D, Vance R. Self-tolerance of natural killer cells. Nat Rev Immunol. 2006;6:520-31 pubmed
    ..Recent studies have produced important new information about NK-cell self-tolerance. Here, we review the evidence for and against possible mechanisms of NK-cell self-tolerance, with an emphasis on the role of MHC-specific receptors. ..
  30. Bala K, Moudgil K. Induction and maintenance of self tolerance: the role of CD4+CD25+ regulatory T cells. Arch Immunol Ther Exp (Warsz). 2006;54:307-21 pubmed
    ..In vitro expansion of antigen-specific CD4(+)CD25(+) T cells and their adoptive transfer into patients suffering from autoimmunity is emerging as a promising new therapeutic approach for these debilitating disorders. ..
  31. Gillard G, Farr A. Contrasting models of promiscuous gene expression by thymic epithelium. J Exp Med. 2005;202:15-9 pubmed
    ..However, as discussed here, an alternative model-whereby TRA expression is regulated by conserved developmental programs active in developing mTECs-may be equally plausible. ..
  32. Gallegos A, Bevan M. Central tolerance: good but imperfect. Immunol Rev. 2006;209:290-6 pubmed
    ..In addition, we recently investigated the efficiency of central tolerance to TSA during ontogeny, and we report that this process was less efficient in neonates than adult animals. ..
  33. Mandik Nayak L, Racz J, Sleckman B, Allen P. Autoreactive marginal zone B cells are spontaneously activated but lymph node B cells require T cell help. J Exp Med. 2006;203:1985-98 pubmed
    ..Therefore, our study of low affinity autoreactive B cells reveals two distinct but potentially concurrent mechanisms for their activation, of which one is T cell dependent and the other is T cell independent. ..
  34. Baecher Allan C, Hafler D. Human regulatory T cells and their role in autoimmune disease. Immunol Rev. 2006;212:203-16 pubmed
    ..In this review, we discuss human natural regulatory T cells, what is known about their function, and their associations with specific autoimmune diseases. ..
  35. Yokoyama W, Kim S. Licensing of natural killer cells by self-major histocompatibility complex class I. Immunol Rev. 2006;214:143-54 pubmed
  36. Kim J, Rasmussen J, Rudensky A. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 2007;8:191-7 pubmed
    ..We suggest that self-reactive T cells are continuously suppressed by T(reg) cells and that when suppression is relieved, self-reactive T cells become activated and facilitate accelerated maturation of dendritic cells. ..
  37. Davalos Misslitz A, Worbs T, Willenzon S, Bernhardt G, Forster R. Impaired responsiveness to T-cell receptor stimulation and defective negative selection of thymocytes in CCR7-deficient mice. Blood. 2007;110:4351-9 pubmed
  38. Wang J, Ioan Facsinay A, van der Voort E, Huizinga T, Toes R. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol. 2007;37:129-38 pubmed
    ..These data indicate that expression of endogenous FOXP3, in humans, is not sufficient to induce regulatory T cell activity or to identify T(reg) cells. ..
  39. Lee J, Epardaud M, Sun J, Becker J, Cheng A, Yonekura A, et al. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat Immunol. 2007;8:181-90 pubmed
    ..Thus, lymph node stromal cells are functionally akin to mTECs and provide a direct strategy for purging the peripheral repertoire of self-reactive T cells. ..
  40. Chen M, Wang Y, Wang Y, Huang L, Sandoval H, Liu Y, et al. Dendritic cell apoptosis in the maintenance of immune tolerance. Science. 2006;311:1160-4 pubmed
    ..The observation that a defect in DC apoptosis can independently lead to autoimmunity is consistent with a central role for these cells in maintaining immune self-tolerance. ..
  41. Huang H, Kearney J, Grusby M, Benoist C, Mathis D. Induction of tolerance in arthritogenic B cells with receptors of differing affinity for self-antigen. Proc Natl Acad Sci U S A. 2006;103:3734-9 pubmed
    ..These studies portray, in a single system, the range of tolerance mechanisms applied to potentially pathogenic B cells, and serve as a base for dissecting where T cell help intervenes and where therapeutic agents impinge. ..
  42. Huehn J, Siegmund K, Hamann A. Migration rules: functional properties of naive and effector/memory-like regulatory T cell subsets. Curr Top Microbiol Immunol. 2005;293:89-114 pubmed
    ..Notably, the potential heterogeneity of Tregs with respect to phenotype and function deserves attention and is a major issue discussed in this review. ..
  43. Meager A, Visvalingam K, Peterson P, Möll K, Murumägi A, Krohn K, et al. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. 2006;3:e289 pubmed
  44. Sohn S, Thompson J, Winoto A. Apoptosis during negative selection of autoreactive thymocytes. Curr Opin Immunol. 2007;19:510-5 pubmed
    ..This and other possibilities will be discussed to explain the unresolved finding that negative selection is defective in Bim(-/-) but is not efficiently blocked in Bcl-2 transgenic mice. ..
  45. Yurasov S, Nussenzweig M. Regulation of autoreactive antibodies. Curr Opin Rheumatol. 2007;19:421-6 pubmed
    ..Discovering the precise nature of B-cell tolerance alterations in patients with autoimmune diseases will lead to the identification of new targets for therapeutic interventions in patients with these disorders. ..
  46. Coutinho A. The Le Douarin phenomenon: a shift in the paradigm of developmental self-tolerance. Int J Dev Biol. 2005;49:131-6 pubmed
  47. Kyewski B, Klein L. A central role for central tolerance. Annu Rev Immunol. 2006;24:571-606 pubmed
  48. Matsumoto M. Transcriptional regulation in thymic epithelial cells for the establishment of self tolerance. Arch Immunol Ther Exp (Warsz). 2007;55:27-34 pubmed
    Thymic epithelial cells (TECs) play pivotal roles in the establishment of self tolerance through critical dialogue with developing thymocytes...
  49. Evel Kabler K, Song X, Aldrich M, Huang X, Chen S. SOCS1 restricts dendritic cells' ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling. J Clin Invest. 2006;116:90-100 pubmed
    ..DC immunization can activate autoreactive T cells but rarely causes autoimmune pathologies, indicating that self tolerance at the host level is still maintained in the vaccinated hosts...
  50. Derbinski J, Gäbler J, Brors B, Tierling S, Jonnakuty S, Hergenhahn M, et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med. 2005;202:33-45 pubmed
    ..Our data document a remarkable cellular and molecular specialization of the thymic stroma in order to mimic the transcriptome of multiple peripheral tissues and, thus, maximize the scope of central self-tolerance. ..
  51. Tomer Y. Hepatitis C and interferon induced thyroiditis. J Autoimmun. 2010;34:J322-6 pubmed publisher
    ..While the epidemiology and clinical presentation of HCV and interferon induced thyroiditis have been well characterized, the mechanisms causing these conditions are still poorly understood. ..
  52. Baumgarth N. The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat Rev Immunol. 2011;11:34-46 pubmed publisher
  53. Walker J, Smith K. CD22: an inhibitory enigma. Immunology. 2008;123:314-25 pubmed
    ..We review the current evidence for this, and discuss the importance of genetic background in modifying CD22 function and predisposition to autoimmunity. ..