Skip to main content
SpringerLink
Log in

Biochemical features of anergic T cells

  • Foreword
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

T cell anergy is a functionally defined state of hyporesponsiveness in which T cells neither proliferate nor produce IL2 following subsequent TCR ligation. Recent biochemical data from in vitro studies suggest that anergic cells do not utilize all of the signaling pathways normally initiated by TCR triggering. These findings appear to hold true for T cells rendered anergic in vivo, as well; however, biochemical studies on clonal anergy in vivo have been limited by the inability to recover a homogeneous population of anergic T cells. Here we review progress on TCR mediated signaling pathways as well as the description of surface marker phenotypes specific to T cell anergy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Reference

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

    Article  PubMed  CAS  Google Scholar 

  2. Jones LA, Chin LT, Longo DL, Kruisbeek AM: Peripheral clonal elimination of functional T-cells. Science 1990;250:1726–1729.

    Article  PubMed  CAS  Google Scholar 

  3. Lo D, Burkly LC, Widera G, Cowing C, Flavell RA, Palmiter RD, et al.: Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic beta cells. Cell 1988;53:159–168.

    Article  PubMed  CAS  Google Scholar 

  4. Webb S, Morris C, Sprent J: Extra-thymic tolerance of mature T-cells: clonal elimination as a consequence of immunity. Cell 1990;63: 1249–1256.

    Article  PubMed  CAS  Google Scholar 

  5. Schonrich G, Kalinke U, Momburg F, Malissen M, Schmitt-Verhulst AM, Malissen B, et al.: Down-regulation of T-cell receptors on self-reactive T-cells as a novel mechanism for extrathymic tolerance induction. Cell 1991;65:293–304.

    Article  PubMed  CAS  Google Scholar 

  6. Rammensee HG, Kroschewski R, Frangoulis B: Clonal anergy induced in mature VΒ6+ T lymphocytes on immunizing Mls-lb mice with Mls-la expressing cells. Nature 1989;339:541–544.

    Article  PubMed  CAS  Google Scholar 

  7. Kappler JW, Staerz U, White J, Marrack PC: Self-tolerance eliminates T-cells specific for Mis-modified products of the major histocompatibility complex. Nature 1988;332:35–40.

    Article  PubMed  CAS  Google Scholar 

  8. Mondino A, Khoruts A, Jenkins MK: The anatomy of T-cell activation and tolerance. Proc Natl Acad Sci USA 1996;93:2245–2252.

    Article  PubMed  CAS  Google Scholar 

  9. Miller A, Zhang ZJ, Sobel RA, alSabbagh A, Weiner HL: Suppression of experimental autoimmune enceph-alomyelitis by oral administration of myelin basic protein. VI. Suppression of adoptively transferred disease and differential effects of oral vs. intravenous tolerization. J Neuroimmunol 1993;46:73–82.

    Article  PubMed  CAS  Google Scholar 

  10. Qin S, Cobbold SP, Pope H, Elliot J, Kioussis D, Davies J, et al.: “Infectious” transplantation tolerance. Science 1993;259:974–977.

    Article  PubMed  CAS  Google Scholar 

  11. Schwartz RH: A cell culture model for T lymphocyte clonal anergy. Science 1990;248:

  12. Quill H, Schwartz RH: Stimulation of normal inducer T-cell clones with antigen presented by purified Ia molecules in planar lipid membranes: specific induction of a long-lived state of proliferative nonresponsiveness. J Immunol 1987;138:3704–3712.

    PubMed  CAS  Google Scholar 

  13. Jenkins MK, Schwartz RH: Antigen presentation by chemically modified splenocytes induces antigen-specific T-cell unresponsiveness in vitro and in vivo. J Exp Med 1987; 165:302–319.

    Article  PubMed  CAS  Google Scholar 

  14. June CH, Bluestone JA, Nadler LM, Thompson CB: The B7 and CD28 receptor families. Immunol Today 1994;15:321–331.

    Article  PubMed  CAS  Google Scholar 

  15. Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP: CD28-mediated signalling co-stimulates murine T-cells and prevents induction of anergy in T-cell clones. Nature 1992;356:607–609.

    Article  PubMed  CAS  Google Scholar 

  16. Linsley PS, Greene JL, Tan P, Bradshaw J, Ledbetter JA, Anasetti C, etal.: Coexpressionandfunctional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med 1992;176:1595–1604.

    Article  PubMed  CAS  Google Scholar 

  17. Sloan-Lancaster J, Allen PM: Altered peptide ligand-induced partial T-cell activation: molecular mechanisms and role in T-cell biology. Annu Rev Immunol 1996;14:l-27.

    Article  Google Scholar 

  18. Schwartz RH: Models of T-cell anergy: is there a common molecular mechanism? J Exp Med 1996;184:l-8.

    Article  Google Scholar 

  19. MacDonald HR, Schneider R, Lees RK, Howe RC, Acha-Orbea H, Festenstein H, et al.: T-cell receptor Vb use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature 1988, 332:40–45.

    Article  PubMed  CAS  Google Scholar 

  20. Webb SR, O’Rourke AM, Sprent J: Factors influencing the fate of T-cells responding to Mls antigens. Semin Immunol 1992;4:329–336.

    PubMed  CAS  Google Scholar 

  21. MacDonald HR, Pedrazzini T, Schneider R, Louis JA, Zinkernagel RM, Hengartner H: Intrathymic elimination of Mlsa-reactive (VΒ6+) cells during neonatal tolerance induction to Mlsa-encoded antigens. J Exp Med 1988;167:2005–2010.

    Article  PubMed  CAS  Google Scholar 

  22. Dannecker G, Mecheri S, Staiano-Coico L, Hoffmann MK: A characteristic Mls-la response precedes Mls-la anergy in vivo. J Immunol 1991;146:2083–2087.

    PubMed  CAS  Google Scholar 

  23. Le Bon A, Lucas B, Vasseur F, Penit C, Papiernik M: In vivo T-cell response to viral superantigen. Selective migration rather than proliferation. J Immunol 1996; 156:4602–4608.

    PubMed  CAS  Google Scholar 

  24. Webb SR, Hutchinson J, Hayden K, Sprent J: Expansion/deletion of mature T-cells exposed to endogenous superantigens in vivo. J Immunol 1994;152:586–597.

    PubMed  CAS  Google Scholar 

  25. Sundstedt A, Dohlsten M, Hedlund G, Hoiden I, Bjorklund M, Kalland T: Superantigens anergize cytokine production but not cytotoxicity in vivo. Immunology 1994;82:117–125.

    PubMed  CAS  Google Scholar 

  26. MacDonald HR, Baschieri S, Lees RK: Clonal expansion precedes anergy and death of VΒ8+ peripheral T-cells responding to staphylococcal enterotoxin B in vivo. Eur J Immunol 1991;21:1963–1966.

    Article  PubMed  CAS  Google Scholar 

  27. Kawabe Y, Ochi A: Programmed cell death and extrathymic reduction of VΒ8+ CD4+ T-cells in mice tolerant toStaphylococcus aureus enterotoxin B. Nature 1991;349: 245–248.

    Article  PubMed  CAS  Google Scholar 

  28. Lee WT, Vitetta ES: Memory T-cells are anergic to the superantigen staphylococcal enterotoxin B. J Exp Med 1992;176:575–579.

    Article  PubMed  CAS  Google Scholar 

  29. Yui K, Komori S, Katsumata M, Siegel RM, Greene MI: Selfreactive T-cells can escape clonal deletion in T-cell receptor Vb8.1 transgenic mice. Proc Natl Acad Sci USA 1990;87:7135–7139.

    Article  PubMed  CAS  Google Scholar 

  30. Blackman MA, Gerhard-Burgert H, Woodland DL, Palmer E, Kappler JW, Marrack P: A role for clonal inactivation in T-cell tolerance to Mls-la. Nature 1990; 345:540–542.

    Article  PubMed  CAS  Google Scholar 

  31. Blackman MA, Finkel TH, Kappler J, Cambier J, Marrack P: Altered antigen receptor signaling in anergic T-cells from selftolerant T-cell receptor Β-chain transgenic mice. Proc Natl Acad Sci USA 1991;88:6682–6686.

    Article  PubMed  CAS  Google Scholar 

  32. Yui K, Katsumata M, Komori S, Gill-Morse L, Greene MI: Response of Vb8.1+ T-cell clones to self Mls-la: implications for the origin of autoreactive T-cells. Int Immunol 1992;4:125–133.

    Article  PubMed  CAS  Google Scholar 

  33. Vacchio MS, Kanagawa O, Tomonari K, Hodes RJ: Influence of T-cell receptor Va expression on Mlsa superantigen-specific T-cell responses. J Exp Med. 1992;175:1405–1408.

    Article  PubMed  CAS  Google Scholar 

  34. Blackman MA, Smith HP, Le P, Woodland DL: Influence of the T-cell receptor α-chain on T-cell reactivity and tolerance to Mls-l in T-cell receptor Β-chain transgenic mice. J Immunol 1993;151:556–565.

    PubMed  CAS  Google Scholar 

  35. Smith HP, Le P, Woodland DL, Blackman MA: T-cell receptor αchain influences reactivity to Mls-1 in VΒ 8.1 transgenic mice. J Immunol 1992;149:887–896.

    PubMed  CAS  Google Scholar 

  36. Daly K, Nguyen P, Hankley D, Zhang WJ, Woodland DL, Blackman MA: Contribution of the TCR a-chain to the differential recognition of bacterial and retroviral superantigens. J Immunol 1995;155:27–34.

    PubMed  CAS  Google Scholar 

  37. Hammerling GJ, Schonrich G, Momburg F, Auphan N, Malissen M, Malissen B, et al.: Non-deletional mechanisms of peripheral and central tolerance: studies with transgenic mice with tissuespecific expression of a foreign MHC class I antigen. Immunol Rev 1991;122:47–67.

    Article  PubMed  CAS  Google Scholar 

  38. Bhandoola A, Cho EA, Yui K, Saragovi HU, Greene MI, Quill H: Reduced CD3-mediated protein tyrosine phosphorylation in anergic CD4+ and CD8+T-cells. J Immunol 1993;151:2355–2367.

    PubMed  CAS  Google Scholar 

  39. Bhandoola A, Bassiri H, Markmann JF, Yui K, Hashimoto Y, Greene MI: Delayed allograft rejection by T-cell receptor Vb 8.1 transgenic mice peripherally tolerized to Mls-l. Eur J Immunol. 1994;24:1710–1713.

    Article  PubMed  CAS  Google Scholar 

  40. Downward J, Graves J, Cantrell D: The regulation and function of p21ras in T-cells. Immunol Today 1992;13:89–92.

    Article  PubMed  CAS  Google Scholar 

  41. Cantrell D: T-cell antigen receptor signal transduction pathways. Annu Rev Immunol 1996;14:259–274.

    Article  PubMed  CAS  Google Scholar 

  42. Sloan-Lancaster J, Shaw AS, Rothbard JB, Allen PM: Partial T-cell signaling: altered phospho-ζ and lack of Zap70 recruitment in APL-induced T-cell anergy. Cell 1994;79:913–922.

    Article  PubMed  CAS  Google Scholar 

  43. Madrenas J, Wange RL, Wang JL, Isakov N, Samelson LE, Germain RN: ζ phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists. Science 1995;267:515–518.

    Article  PubMed  CAS  Google Scholar 

  44. Boussiotis VA, Barber DL, Lee BJ, Gribben JG, Freeman GJ, Nadler LM: Differential association of protein tyrosine kinases with the T-cell receptor is linked to the induction of anergy and its prevention by B7 family-mediated costimulation. J Exp Med. 1996; 184:365–376.

    Article  PubMed  CAS  Google Scholar 

  45. Quill H, Riley MP, Cho EA, Casnellie JE, Reed JC, Torigoe T: Anergic Th1 cells express altered levels of the protein tyrosine kinases p56lck and p59fyn. J Immunol 1992;149:2887–2893.

    PubMed  CAS  Google Scholar 

  46. Gajewski TF, Qian D, Fields P, Fitch FW: Anergic T-lymphocyte clones have altered inositol phosphate, calcium, and tyrosine kinase signaling pathways. Proc Natl Acad Sci USA 1994;91:38–42.

    Article  PubMed  CAS  Google Scholar 

  47. LaFace DM, Couture C, Anderson K, Shih G, Alexander J, Sette A, et al.: Differential T-cell signaling induced by antagonist peptide-MHC complexes and the associated phenotypic responses. J Immunol. 1997;158:2057–2064.

    CAS  Google Scholar 

  48. Kersh GJ, Allen PM: Essential flexibility in the T-cell recognition of antigen. Nature 1996;380:495–498.

    Article  PubMed  CAS  Google Scholar 

  49. Janeway CA Jr., Bottomly K: Signals and signs for lymphocyte responses. Cell 1994;76:275–285.

    Article  PubMed  CAS  Google Scholar 

  50. Madrenas J, Chau LA, Smith J, Bluestone JA, Germain RN: The efficiency of CD4 recruitment to ligand-engaged TCR controls the agonist/partial agonist properties of peptide-MHC molecule ligands. J Exp Med 1997;185:219–229.

    Article  PubMed  CAS  Google Scholar 

  51. Lyons DS, Lieberman SA, Hampl J, Boniface JJ, Chien Y, Berg LJ, et al.: A TCR binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists. Immunity 1996;5:51–59.

    Article  Google Scholar 

  52. Sloan-Lancaster J, Steinberg TH, Allen PM: Selective activation of the calcium signaling pathway by altered peptide ligands. J Exp Med 1996;184:1525–1530.

    Article  PubMed  CAS  Google Scholar 

  53. Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI:Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 1997;386: 855–858.

    Article  PubMed  CAS  Google Scholar 

  54. Berridge MJ: The AM and FM of calcium signalling. Nature 1997; 386:759,760.

    Article  Google Scholar 

  55. Fields PE, Gajewski TF, Fitch FW: Blocked Ras activation in anergic CD4+T-cells. Science 1996;271: 1276–1278.

    Article  PubMed  CAS  Google Scholar 

  56. Li W, Whaley CD, Mondino A, Mueller DL:Blocked signal transduction to the ERK and JNK protein kinases in anergic CD4+ T-cells. Science 1996;271:1272–1276.

    Article  PubMed  CAS  Google Scholar 

  57. Kang SM, Beverly B, Tran AC, Brorson K, Schwartz RH, Lenardo MJ: Transactivation by AP-1 is a molecular target of T-cell clonal anergy. Science 1992;257:1134–1138.

    Article  PubMed  CAS  Google Scholar 

  58. Go C, Miller J: Differential induction of transcription factors that regulate the interleukin 2 gene during anergy induction and restimulation. J Exp Med 1992; 175:1327–1336.

    Article  PubMed  CAS  Google Scholar 

  59. Wotton D, Higgins JA, O’Hehir RE, Lamb JR, Lake RA: Differential induction of the NF-AT complex during restimulation and the induction of T-cell anergy. Hum Immunol 1995;42:95–102.

    Article  PubMed  CAS  Google Scholar 

  60. Becker JC, Brabletz T, Kirchner T, Conrad CT, Brocker EB, Reisfeld RA: Negative transcriptional regulation in anergic T-cells. Proc Natl Acad Sci USA 1995;92:2375–2378.

    Article  PubMed  CAS  Google Scholar 

  61. Migita K, Eguchi K, Kawabe Y, Tsukada T, Ichinose Y, Nagataki S: Defective TCR-mediated signaling in anergic T-cells. J Immunol 1995;155:5083–5087.

    PubMed  CAS  Google Scholar 

  62. Yui K, Ishida Y, Katsumata M, Komori S, Chused TM, Abe R: Two separate mechanisms of T-cell clonal anergy to Mls-l. J Immunol 1993;151:6062–6075.

    PubMed  CAS  Google Scholar 

  63. Sundstedt A, Sigvardsson M, Leanderson T, Hedlund G, Kalland T, Dohlsten M: In vivo anergized CD4+ T-cells express perturbed AP-1 and NF-kB transcription factors. Proc Natl Acad Sci USA 1996;93: 979–984.

    Article  PubMed  CAS  Google Scholar 

  64. Scharenberg AM, Kinet J-P: The emerging field of receptor-mediated inhibitory signaling: SHPSHIP? Cell 1996;87:961–964.

    Article  PubMed  CAS  Google Scholar 

  65. Plas DR, Johnson R, Pingel JT, Matthews RJ, Dalton M, Roy G, et al.: Direct regulation of ZAP-70 by SHP-1 in T-cell antigen receptor signaling. Science 1996;272:1173–1176.

    Article  PubMed  CAS  Google Scholar 

  66. Marengere LE, Waterhouse P, Duncan GS, Mittrucker HW, Feng GS, Mak TW: Regulation of T-cell receptor signaling by tyrosine phosphatase SYP association with CTLA -4. Science 1996;272:1170–1173.

    Article  PubMed  CAS  Google Scholar 

  67. Beverly B, Kang SM, Lenardo MJ, Schwartz RH: Reversal of in vitro T-cell clonal anergy by IL-2 stimulation. Int Immunol. 1992;4:661–671.

    Article  PubMed  CAS  Google Scholar 

  68. Vitetta ES, Berton MT, Burger C, Kepron M, Lee WT, Yin X-M: Memory T and B cells. Annu Rev Immunol 1991;9:193–217.

    Article  PubMed  CAS  Google Scholar 

  69. Hayden KA, Tough DF, Webb SR: In vivo response of mature T-cells to Mlsa antigens. Long-term progeny of dividing cells include cells with a naive phenotype. J Immunol 1996;156:48–55.

    PubMed  CAS  Google Scholar 

  70. Hayakawa K, Hardy RR: Murine CD4+ T-cell subsets defined. J Exp Med 1988;168:1825–1838.

    Article  PubMed  CAS  Google Scholar 

  71. Hayakawa K, Hardy RR: Murine CD4+ T-cell subsets. Immunol Rev 1991;123:145–168.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA

    Curtis C. Maier &  Mark I. Greene

  2. Dept. of Pathol., Div. of Immunol., 252 John Morgan Building, 19104-6082, Philadelphia, PA

    Mark I. Greene

Authors
  1. Curtis C. Maier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark I. Greene
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maier, C.C., Greene, M.I. Biochemical features of anergic T cells. Immunol Res 17, 133–140 (1998). https://doi.org/10.1007/BF02786438

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02786438

Key words

Search

Navigation