clonal anergy


Summary: Functional inactivation of T- or B-lymphocytes rendering them incapable of eliciting an immune response to antigen. This occurs through different mechanisms in the two kinds of lymphocytes and can contribute to SELF TOLERANCE.

Top Publications

  1. Martinez R, Zhang N, Thomas S, Nandiwada S, Jenkins M, Binstadt B, et al. Arthritogenic self-reactive CD4+ T cells acquire an FR4hiCD73hi anergic state in the presence of Foxp3+ regulatory T cells. J Immunol. 2012;188:170-81 pubmed publisher
    ..T cell lymphopenia has also been shown to be a barrier to CD4(+) T cell clonal anergy induction...
  2. Kline J, Brown I, Zha Y, Blank C, Strickler J, Wouters H, et al. Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma. Clin Cancer Res. 2008;14:3156-67 pubmed publisher
    ..Our results indicate that combined CD25 depletion and homeostatic proliferation support a potent antitumor immune response--an approach with potential for clinical translation. ..
  3. Lin A, Mak T. The role of E3 ligases in autoimmunity and the regulation of autoreactive T cells. Curr Opin Immunol. 2007;19:665-73 pubmed
    ..Findings emerging from these investigations may suggest ways to exploit the therapeutic potential of manipulating ubiquitination, particularly for autoimmune disorders. ..
  4. Saibil S, Deenick E, Ohashi P. The sound of silence: modulating anergy in T lymphocytes. Curr Opin Immunol. 2007;19:658-64 pubmed
    ..Thus, the emerging view is that T cell anergy is a dynamic state whose establishment and maintenance can be influenced by numerous different signaling pathways. ..
  5. Merrell K, Benschop R, Gauld S, Aviszus K, Decote Ricardo D, Wysocki L, et al. Identification of anergic B cells within a wild-type repertoire. Immunity. 2006;25:953-62 pubmed
    ..In conclusion, our findings indicate that anergy is probably the primary mechanism by which autoreactive B cells are silenced. Thus maintenance of the unresponsiveness of anergic cells is critical for prevention of autoimmunity...
  6. Broderick L, Brooks S, Takita H, Baer A, Bernstein J, Bankert R. IL-12 reverses anergy to T cell receptor triggering in human lung tumor-associated memory T cells. Clin Immunol. 2006;118:159-69 pubmed
  7. Quezada S, Bennett K, Blazar B, Rudensky A, Sakaguchi S, Noelle R. Analysis of the underlying cellular mechanisms of anti-CD154-induced graft tolerance: the interplay of clonal anergy and immune regulation. J Immunol. 2005;175:771-9 pubmed
    ..Finally, it is shown that the suppression is long-lived, and in the absence of anti-CD154 and donor-specific transfusion, these T(reg) can chronically suppress effector cell responses, allowing long-lived graft acceptance. ..
  8. Safford M, Collins S, Lutz M, Allen A, Huang C, Kowalski J, et al. Egr-2 and Egr-3 are negative regulators of T cell activation. Nat Immunol. 2005;6:472-80 pubmed
    ..These data support the idea that Egr-2 and Egr-3 are involved in promoting a T cell receptor-induced negative regulatory genetic program. ..
  9. Zikherman J, Doan K, Parameswaran R, Raschke W, Weiss A. Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival. Proc Natl Acad Sci U S A. 2012;109:E3-12 pubmed publisher
    ..Taken together, our findings reveal how CD45 function diverges in T cells and B cells, as well as how autoreactive B cells are censored as they transit development. ..

More Information


  1. Delgoffe G, Powell J. mTOR: taking cues from the immune microenvironment. Immunology. 2009;127:459-65 pubmed publisher
    ..Specifically, we review the role of mTOR in promoting dendritic cell activation and maturation, in regulating full T cell activation versus anergy, and influencing the induction of regulatory T cells. ..
  2. Sacchi A, Tempestilli M, Turchi F, Agrati C, Casetti R, Cimini E, et al. CD3zeta down-modulation may explain Vgamma9Vdelta2 T lymphocyte anergy in HIV-infected patients. J Infect Dis. 2009;199:432-6 pubmed publisher
    ..Our findings may contribute to clarification of the molecular mechanisms of Vgamma9Vdelta2 T cell anergy found in HIV-positive patients. ..
  3. Wherry E, Ha S, Kaech S, Haining W, Sarkar S, Kalia V, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007;27:670-84 pubmed
    ..Thus, functional exhaustion is probably due to both active suppression and passive defects in signaling and metabolism. These results provide a framework for designing rational immunotherapies during chronic infections. ..
  4. Bandyopadhyay S, Dure M, Paroder M, Soto Nieves N, Puga I, Macian F. Interleukin 2 gene transcription is regulated by Ikaros-induced changes in histone acetylation in anergic T cells. Blood. 2007;109:2878-86 pubmed
    ..We propose a model in which tolerizing stimuli induce epigenetic changes on the interleukin 2 locus that are responsible for the stable inhibition of the expression of this cytokine in anergic T cells. ..
  5. Choi S, Schwartz R. Molecular mechanisms for adaptive tolerance and other T cell anergy models. Semin Immunol. 2007;19:140-52 pubmed
    ..In this review we will detail our own work on the in vivo model referred to as adaptive tolerance and then attempt to compare this biochemical state to the multitude of other states that have been described in the literature. ..
  6. Blery M, Tze L, Miosge L, Jun J, Goodnow C. Essential role of membrane cholesterol in accelerated BCR internalization and uncoupling from NF-kappa B in B cell clonal anergy. J Exp Med. 2006;203:1773-83 pubmed
    ..These results provide a possible explanation for the signaling changes in clonal anergy and indicate that a chief function of membrane cholesterol in B cells is not to initiate BCR signaling, but ..
  7. Boon T, Coulie P, van den Eynde B, van der Bruggen P. Human T cell responses against melanoma. Annu Rev Immunol. 2006;24:175-208 pubmed
    ..In patients who do respond to the vaccine, the antivaccine T cells probably succeed in reversing focally this immunosuppression and trigger a broad activation of other antitumor T cells, which proceed to destroy the tumor. ..
  8. Schneider H, Valk E, Leung R, Rudd C. CTLA-4 activation of phosphatidylinositol 3-kinase (PI 3-K) and protein kinase B (PKB/AKT) sustains T-cell anergy without cell death. PLoS ONE. 2008;3:e3842 pubmed publisher
    ..Our findings therefore define a mechanism by which CTLA-4 can induce anergy (and possibly peripheral tolerance) by preventing the induction of cell death. ..
  9. Zha Y, Marks R, Ho A, Peterson A, Janardhan S, Brown I, et al. T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-alpha. Nat Immunol. 2006;7:1166-73 pubmed
    ..Our data support a causal function for excess DGK activity and defective Ras signaling in T cell anergy. ..
  10. Quách T, Manjarrez Orduno N, Adlowitz D, Silver L, Yang H, Wei C, et al. Anergic responses characterize a large fraction of human autoreactive naive B cells expressing low levels of surface IgM. J Immunol. 2011;186:4640-8 pubmed publisher
  11. Duty J, Szodoray P, Zheng N, Koelsch K, Zhang Q, Swiatkowski M, et al. Functional anergy in a subpopulation of naive B cells from healthy humans that express autoreactive immunoglobulin receptors. J Exp Med. 2009;206:139-51 pubmed publisher
    ..This is the first identification of a distinct mature human B cell subset that is naturally autoreactive and controlled by the tolerizing mechanism of functional anergy. ..
  12. Olenchock B, Guo R, Carpenter J, Jordan M, Topham M, Koretzky G, et al. Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nat Immunol. 2006;7:1174-81 pubmed
    ..Our findings suggest that regulation of diacylglycerol metabolism is critical in determining whether activation or anergy ensues after T cell receptor stimulation. ..
  13. Brown I, Blank C, Kline J, Kacha A, Gajewski T. Homeostatic proliferation as an isolated variable reverses CD8+ T cell anergy and promotes tumor rejection. J Immunol. 2006;177:4521-9 pubmed
    ..Taken together, our data suggest that a major mechanism by which homeostatic proliferation supports tumor rejection is by maintaining and/or re-establishing T cell responsiveness. ..
  14. Tan P, Sagoo P, Chan C, Yates J, Campbell J, Beutelspacher S, et al. Inhibition of NF-kappa B and oxidative pathways in human dendritic cells by antioxidative vitamins generates regulatory T cells. J Immunol. 2005;174:7633-44 pubmed
    ..These data indicate that vitamin C- and E-treated DC might be useful for the induction of tolerance to allo- or autoantigens. ..
  15. Fathman C, Lineberry N. Molecular mechanisms of CD4+ T-cell anergy. Nat Rev Immunol. 2007;7:599-609 pubmed
    ..Controlling anergy induction and maintenance will be a key component in the future to mitigate unwanted T-cell activation that leads to autoimmune disease. ..
  16. Gauld S, Merrell K, Cambier J. Silencing of autoreactive B cells by anergy: a fresh perspective. Curr Opin Immunol. 2006;18:292-7 pubmed
    ..Thus, the time-honored two-signal hypothesis is almost certainly correct, with second signals being required to release the cell from inhibitory BCR-specific and trans-active feedback regulation. ..
  17. Kubach J, Lutter P, Bopp T, Stoll S, Becker C, Huter E, et al. Human CD4+CD25+ regulatory T cells: proteome analysis identifies galectin-10 as a novel marker essential for their anergy and suppressive function. Blood. 2007;110:1550-8 pubmed
    ..Notably, first identified here as expressed in human T lymphocytes, galectin-10 is essential for the functional properties of CD25(+) Treg cells. ..
  18. Venuprasad K, Elly C, Gao M, Salek Ardakani S, Harada Y, Luo J, et al. Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation. J Clin Invest. 2006;116:1117-26 pubmed
    ..This study suggests that MEKK1-JNK signaling regulates Itch E3 ligase-mediated tolerogenic process in Th2 cells. These findings have therapeutic implications for allergic diseases. ..
  19. Yarkoni Y, Getahun A, Cambier J. Molecular underpinning of B-cell anergy. Immunol Rev. 2010;237:249-63 pubmed publisher
  20. Demotte N, Stroobant V, Courtoy P, Van Der Smissen P, Colau D, Luescher I, et al. Restoring the association of the T cell receptor with CD8 reverses anergy in human tumor-infiltrating lymphocytes. Immunity. 2008;28:414-24 pubmed publisher
    ..The separation of TCR and CD8 molecules could be one major mechanism of anergy in tumors and other chronic stimulation conditions. ..
  21. Rowell E, Walsh M, Wells A. Opposing roles for the cyclin-dependent kinase inhibitor p27kip1 in the control of CD4+ T cell proliferation and effector function. J Immunol. 2005;174:3359-68 pubmed
    ..Our results suggest that p27kip1 plays a complex and important role in the regulation of cell division and effector function in primary CD4+ T cells. ..
  22. Cambier J, Gauld S, Merrell K, Vilen B. B-cell anergy: from transgenic models to naturally occurring anergic B cells?. Nat Rev Immunol. 2007;7:633-43 pubmed
    ..In this Review, we compare and contrast the salient features of anergic B cells with a view to developing unifying mechanistic hypotheses that explain their lifestyles. ..
  23. Goodnow C, Sprent J, Fazekas de St Groth B, Vinuesa C. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature. 2005;435:590-7 pubmed
    ..This provides the bridge between clinical studies and mechanisms defined in experimental animals to understand how sets of gene products coordinate self-tolerance mechanisms and how defects in these controls lead to autoimmune disease. ..
  24. Gauld S, Benschop R, Merrell K, Cambier J. Maintenance of B cell anergy requires constant antigen receptor occupancy and signaling. Nat Immunol. 2005;6:1160-7 pubmed
    ..Our findings indicate that continuous binding of antigen and subsequent receptor signaling are essential for the maintenance of anergy. ..
  25. Norian L, Rodriguez P, O Mara L, Zabaleta J, Ochoa A, Cella M, et al. Tumor-infiltrating regulatory dendritic cells inhibit CD8+ T cell function via L-arginine metabolism. Cancer Res. 2009;69:3086-94 pubmed publisher
    ..Thus, within the tumor microenvironment, MHC II(+) TIDCs can function as potent suppressors of CD8(+) T-cell immunity. ..
  26. Chiodetti L, Choi S, Barber D, Schwartz R. Adaptive tolerance and clonal anergy are distinct biochemical states. J Immunol. 2006;176:2279-91 pubmed
    ..This state was contrasted with T cell clonal anergy in which the RAS/MAPK pathway was preferentially impaired and there was much less inhibition of Zap70 kinase ..
  27. Cappione A, Anolik J, Pugh Bernard A, Barnard J, Dutcher P, Silverman G, et al. Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus. J Clin Invest. 2005;115:3205-16 pubmed
    ..To our knowledge, this work represents the first comparative analysis of the fate of a specific autoreactive human B cell population. The results identify a defective tolerance checkpoint that appears to be specific for human SLE. ..
  28. Carrier Y, Yuan J, Kuchroo V, Weiner H. Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice. J Immunol. 2007;178:179-85 pubmed
    ..Thus, Ag-specific TGF-beta-producing Th3 cells play a crucial role in inducing and maintaining peripheral tolerance by driving the differentiation of Ag-specific Foxp3(+) regulatory cells in the periphery. ..
  29. Wells A. New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting. J Immunol. 2009;182:7331-41 pubmed publisher
  30. Sato K, Yamashita N, Baba M, Matsuyama T. Modified myeloid dendritic cells act as regulatory dendritic cells to induce anergic and regulatory T cells. Blood. 2003;101:3581-9 pubmed
    ..Thus, the modulation of T cell-mediated immunity by regulatory DCs provides a novel therapeutic approach for immunopathogenic diseases. ..
  31. Colombetti S, Benigni F, Basso V, Mondino A. Clonal anergy is maintained independently of T cell proliferation. J Immunol. 2002;169:6178-86 pubmed the absence of proliferation results in the establishment of T cell unresponsiveness, also known as T cell clonal anergy. Anergic T cells fail to proliferate upon restimulation because of the inability to produce IL-2 and to ..
  32. Lieberman J, Manjunath N, Shankar P. Avoiding the kiss of death: how HIV and other chronic viruses survive. Curr Opin Immunol. 2002;14:478-86 pubmed
    ..The chance to eradicate an infection by T cell mediated lysis is undermined after an infection becomes established, in part because the effector immune response is impaired in the setting of chronic antigen. ..
  33. Macian F, Garcia Cozar F, Im S, Horton H, Byrne M, Rao A. Transcriptional mechanisms underlying lymphocyte tolerance. Cell. 2002;109:719-31 pubmed
    ..Thus, in the absence of AP-1, NFAT imposes a genetic program of lymphocyte anergy that counters the program of productive activation mediated by the cooperative NFAT:AP-1 complex. ..
  34. Yamazaki S, Iyoda T, Tarbell K, Olson K, Velinzon K, Inaba K, et al. Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J Exp Med. 2003;198:235-47 pubmed
    ..The capacity to expand CD25+ CD4+ T cells provides DCs with an additional mechanism to regulate autoimmunity and other immune responses. ..
  35. Macian F, Im S, García Cózar F, Rao A. T-cell anergy. Curr Opin Immunol. 2004;16:209-16 pubmed
    ..These studies have helped clarify the nature of the signals that induce tolerance, the cells able to deliver them and the molecular processes that underlie the unresponsive state. ..
  36. Ohkusu Tsukada K, Tominaga N, Udono H, Yui K. Regulation of the maintenance of peripheral T-cell anergy by TAB1-mediated p38 alpha activation. Mol Cell Biol. 2004;24:6957-66 pubmed
    ..These results imply that TAB1-mediated activation of p38 alpha in anergic T cells regulates the maintenance of T-cell unresponsiveness both by inhibiting IL-2 production and by promoting IL-10 production. ..
  37. Jeon M, Atfield A, Venuprasad K, Krawczyk C, Sarao R, Elly C, et al. Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity. 2004;21:167-77 pubmed
    ..Our results show a critical role for Cbl-b in the regulation of peripheral tolerance and anergy of T cells. ..
  38. Andris F, Denanglaire S, de Mattia F, Urbain J, Leo O. Naive T cells are resistant to anergy induction by anti-CD3 antibodies. J Immunol. 2004;173:3201-8 pubmed
  39. Harris J, Bishop K, Phillips N, Mordes J, Greiner D, Rossini A, et al. Early growth response gene-2, a zinc-finger transcription factor, is required for full induction of clonal anergy in CD4+ T cells. J Immunol. 2004;173:7331-8 pubmed
    ..These data indicate that sustained Egr-2 expression is necessary to induce a full anergic state through the actions of genes regulated by this transcription factor. ..
  40. Kubsch S, Graulich E, Knop J, Steinbrink K. Suppressor activity of anergic T cells induced by IL-10-treated human dendritic cells: association with IL-2- and CTLA-4-dependent G1 arrest of the cell cycle regulated by p27Kip1. Eur J Immunol. 2003;33:1988-97 pubmed
    ..Our data show that regulatory function of anergic CD4+ suppressor T cells is associated with an arrest in the G1 phase of the cell cycle mediated by increased levels of the IL-2- and CTLA-4-dependent cdk inhibitor p27Kip1. ..
  41. Karsunky H, Merad M, Cozzio A, Weissman I, Manz M. Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid-committed progenitors to Flt3+ dendritic cells in vivo. J Exp Med. 2003;198:305-13 pubmed
  42. Walker L, Chodos A, Eggena M, Dooms H, Abbas A. Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J Exp Med. 2003;198:249-58 pubmed
    ..These observations support a model in which Treg population dynamics are shaped by the local antigenic environment. ..
  43. Stamou P, de Jersey J, Carmignac D, Mamalaki C, Kioussis D, Stockinger B. Chronic exposure to low levels of antigen in the periphery causes reversible functional impairment correlating with changes in CD5 levels in monoclonal CD8 T cells. J Immunol. 2003;171:1278-84 pubmed
    ..This suggests that up-regulation of negative T cell regulators in peripheral T cells exposed to chronic stimulation by Ag may prevent full functionality and thus avoid overt autoreactivity. ..
  44. Acevedo Suárez C, Hulbert C, Woodward E, Thomas J. Uncoupling of anergy from developmental arrest in anti-insulin B cells supports the development of autoimmune diabetes. J Immunol. 2005;174:827-33 pubmed
    ..These findings suggest that the degree of functional impairment, rather than an overt breach of tolerance, is a critical feature that governs B cell contribution to T cell-mediated autoimmune disease. ..
  45. Rivoltini L, Carrabba M, Huber V, Castelli C, Novellino L, Dalerba P, et al. Immunity to cancer: attack and escape in T lymphocyte-tumor cell interaction. Immunol Rev. 2002;188:97-113 pubmed
    ..Finally, we discuss the role of inducible nitric oxide synthases in determining the inhibition of apoptosis in melanoma cells, which can make such tumor cells resistant to the T-cell attack. ..
  46. Sundstedt A, O Neill E, Nicolson K, Wraith D. Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo. J Immunol. 2003;170:1240-8 pubmed
    ..These results emphasize an important role for IL-10 in the function of peptide-induced regulatory T cells in vivo and highlight the caution required in extrapolating mechanisms of T regulatory cell function from in vitro studies. ..
  47. Crespi D, Massa S, Basso V, Colombetti S, Mueller D, Mondino A. Constitutive active p21ras enhances primary T cell responsiveness to Ca2+ signals without interfering with the induction of clonal anergy. Eur J Immunol. 2002;32:2500-9 pubmed
    Chronic engagement of the T cell receptor mediates the induction of T lymphocyte unresponsiveness called clonal anergy. The development of such unresponsiveness has been suggested as one of the mechanisms that regulate peripheral ..
  48. Ekland E, Forster R, Lipp M, Cyster J. Requirements for follicular exclusion and competitive elimination of autoantigen-binding B cells. J Immunol. 2004;172:4700-8 pubmed
    ..These findings characterize the mechanism for follicular exclusion of autoantigen-binding B cells and they indicate that B cells compete for survival by mechanisms that are separate from competition for the follicular niche. ..
  49. Reichlin A, Gazumyan A, Nagaoka H, Kirsch K, Kraus M, Rajewsky K, et al. A B cell receptor with two Igalpha cytoplasmic domains supports development of mature but anergic B cells. J Exp Med. 2004;199:855-65 pubmed
    ..In addition, Igbetac-->alphac B cells showed decreased proliferative and Ca2+ responses to BCR stimulation in vitro, and were anergic to T-independent and -dependent antigens in vivo. ..
  50. Dieckmann D, Bruett C, Ploettner H, Lutz M, Schuler G. Human CD4(+)CD25(+) regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells [corrected]. J Exp Med. 2002;196:247-53 pubmed
    ..This 'catalytic' function of CD4(+)CD25(+) T cells to induce Tr1-like cells helps to explain their central role for the maintenance of immune homeostasis. ..
  51. Sasaki Y, Sakai M, Miyazaki S, Higuma S, Shiozaki A, Saito S. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Mol Hum Reprod. 2004;10:347-53 pubmed
    ..These results suggest that decidual CD4(+)CD25(bright) T cells contribute to the mechanisms mediating maternal immune tolerance of conceptus antigens and therefore might contribute to the maintenance of pregnancy. ..
  52. Heissmeyer V, Macian F, Im S, Varma R, Feske S, Venuprasad K, et al. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol. 2004;5:255-65 pubmed
    ..Our results define a complex molecular program that links gene transcription induced by calcium and calcineurin to a paradoxical impairment of signal transduction in anergic T cells. ..
  53. Verdoodt B, Blazek T, Rauch P, Schuler G, Steinkasserer A, Lutz M, et al. The cyclin-dependent kinase inhibitors p27Kip1 and p21Cip1 are not essential in T cell anergy. Eur J Immunol. 2003;33:3154-63 pubmed
    ..These data indicate that other cell cycle regulators contribute to the cell cycle arrest of anergic T cells, as neither Cdk inhibitor is required for the induction of anergy. ..