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Transcriptional modulation of TCR, Notch and Wnt signaling pathways in SEB-anergized CD4+ T cells

Genes & Immunity volume 6, pages 596–608 (2005)Cite this article

Abstract

Gene expression changes in CD4 + Vβ8+ T cells anergized by in vivo exposure to staphylococcal enterotoxin B (SEB) bacterial superantigen compared to CD4 + Vβ8+ nonanergic T cells were assessed using DNA microarrays containing 5184 murine complementary DNAs. Anergy in splenic T cells of SEB-immunized BALB/c mice was verified by dramatically reduced proliferative capacity and an 8 × overexpression of GRAIL mRNA in CD4 + Vβ8+ T cells taken from mice 7 days after injection. At an Associative t-test threshold of P<0.0005, 96 genes were overexpressed or detected only in anergic T cells, while 256 genes were suppressed or not detected in anergic T cells. Six of eight differential expressions tested using real-time quantitative PCR were validated. Message for B-Raf was detected only in non-anergic cells, while expression of the TCR signaling modulator Slap (Src-like adapter protein) and the TCR ζ-chain specific phosphatase Ptpn3 was enhanced. Modulation of multiple genes suggests downregulation of Wnt/β-catenin signaling and enhanced Notch signaling in the anergic cells. Consistent with previous reports in a non-superantigen in vivo anergy model, mRNA for CD18 and the transcription factor Satb1 (special AT-rich-binding protein 1) was increased in SEB-anergized T cells. This is the first report of global transcriptional changes in CD4+ T cells made anergic by superantigen exposure.

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References

  1. Nakken B, Davis KE, Pan ZJ, Bachmann M, Farris AD . T-helper cell tolerance to ubiquitous nuclear antigens. Scand J Immunol 2003; 58: 478–492.

    Article  CAS  Google Scholar 

  2. Sloan-Lancaster J, Evavold BD, Allen PM . Th2 cell clonal anergy as a consequence of partial activation. J Exp Med 1994; 180: 1195–1205.

    Article  CAS  Google Scholar 

  3. Mirshahidi S, Huang CT, Sadegh-Nasseri S . Anergy in peripheral memory CD4(+) T cells induced by low avidity engagement of T cell receptor. J Exp Med 2001; 194: 719–731.

    Article  CAS  Google Scholar 

  4. Rellahan BL, Jones LA, Kruisbeek AM, Fry AM, Matis LA . In vivo induction of anergy in peripheral V beta 8+ T cells by staphylococcal enterotoxin B. J Exp Med 1990; 172: 1091–1100.

    Article  CAS  Google Scholar 

  5. 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  CAS  Google Scholar 

  6. Powell JD, Ragheb JA, Kitagawa-Sakakida S, Schwartz RH . Molecular regulation of interleukin-2 expression by CD28 co-stimulation and anergy. Immunol Rev 1998; 165: 287–300.

    Article  CAS  Google Scholar 

  7. Schwartz RH . T cell anergy. Annu Rev Immunol 2003; 21: 305–334.

    Article  CAS  Google Scholar 

  8. Seroogy CM, Fathman CG . T-cell anergy: from phenotype to genotype and back. Immunol Res 2003; 28: 255–264.

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  10. Koide Y, Uchijima M, Yoshida A, Yoshida TO . Effect of staphylococcal enterotoxin B-induced anergy on cytokine gene expression: anergy-sensitive and resistant mRNA expression. J Interferon Cytokine Res 1996; 16: 225–236.

    Article  CAS  Google Scholar 

  11. Kimura M, Yamashita M, Kubo M, Iwashima M, Shimizu C, Tokoyoda K et al. Impaired Ca/calcineurin pathway in vivo anergized CD4T cells. Int Immunol 2000; 12: 817–824.

    Article  CAS  Google Scholar 

  12. Heeg K, Gaus H, Griese D, Bendigs S, Miethke T, Wagner H . Superantigen-reactive T cells that display an anergic phenotype in vitro appear functional in vivo. Int Immunol 1995; 7: 105–114.

    Article  CAS  Google Scholar 

  13. Gonzalez-Garcia A, Marchetti P, Castedo M, Zamzami N, Tarazona R, Martinez AC et al. Polyethylene glycol-modified IL-2 abrogates superantigen-induced anergy without affecting peripheral clonal deletion in vivo. Clin Immunol Immunopathol 1996; 78: 215–222.

    Article  CAS  Google Scholar 

  14. Hamel ME, Eynon EE, Savelkoul HF, van Oudenaren A, Kruisbeek AM . Activation and re-activation potential of T cells responding to staphylococcal enterotoxin B. Int Immunol 1995; 7: 1065–1077.

    Article  CAS  Google Scholar 

  15. Baschieri S, Lees RK, Lussow AR, MacDonald HR . Clonal anergy to staphylococcal enterotoxin B in vivo: selective effects on T cell subsets and lymphokines. Eur J Immunol 1993; 23: 2661–2666.

    Article  CAS  Google Scholar 

  16. Gaus H, Miethke T, Wagner H, Heeg K . Superantigen-induced anergy of V beta 8+ CD4+ T cells induces functional but non-proliferative T cells in vivo. Immunology 1994; 83: 333–340.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Lee WT, Thrush GR, Vitetta ES . Staphylococcal enterotoxin B induces the expression of activation markers on murine memory T cells in the absence of proliferation or lymphokine secretion. Cell Immunol 1995; 162: 26–32.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Yuh K, Siminovitch KA, Ochi A . T cell anergy is programmed early after exposure to bacterial superantigen in vivo. Int Immunol 1993; 5: 1375–1382.

    Article  CAS  Google Scholar 

  20. 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.

    CAS  PubMed  Google Scholar 

  21. Telander DG, Malvey EN, Mueller DL . Evidence for repression of IL-2 gene activation in anergic T cells. J Immunol 1999; 162: 1460–1465.

    CAS  PubMed  Google Scholar 

  22. Seroogy CM, Soares L, Ranheim EA, Su L, Holness C, Bloom D et al. The gene related to anergy in lymphocytes, an E3 ubiquitin ligase, is necessary for anergy induction in CD4T cells. J Immunol 2004; 173: 79–85.

    Article  CAS  Google Scholar 

  23. Heissmeyer V, Macian F, Im SH, Varma R, Feske S, Venuprasad K et al. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol 2004; 5: 255–265.

    Article  CAS  Google Scholar 

  24. Verdoodt B, Blazek T, Rauch P, Schuler G, Steinkasserer A, Lutz MB et al. The cyclin-dependent kinase inhibitors p27Kip1 and p21Cip1 are not essential in T cell anergy. Eur J Immunol 2003; 33: 3154–3163.

    Article  CAS  Google Scholar 

  25. Inobe M, Schwartz RH . CTLA-4 engagement acts as a brake on CD4+ T cell proliferation and cytokine production but is not required for tuning T cell reactivity in adaptive tolerance. J Immunol 2004; 173: 7239–7248.

    Article  CAS  Google Scholar 

  26. Radtke F, Wilson A, Mancini SJ, MacDonald HR . Notch regulation of lymphocyte development and function. Nat Immunol 2004; 5: 247–253.

    Article  CAS  Google Scholar 

  27. Staal FJ, Clevers HC . WNT signalling and haematopoiesis: a WNT–WNT situation. Nat Rev Immunol 2005; 5: 21–30.

    Article  CAS  Google Scholar 

  28. le Gouvello S, Manceau V, Sobel A . Serine 16 of stathmin as a cytosolic target for Ca2+/calmodulin-dependent kinase II after CD2 triggering of human T lymphocytes. J Immunol 1998; 161: 1113–1122.

    CAS  PubMed  Google Scholar 

  29. Rubin CI, Atweh GF . The role of stathmin in the regulation of the cell cycle. J Cell Biochem 2004; 93: 242–250.

    Article  CAS  Google Scholar 

  30. Dahle MK, Gronning LM, Cederberg A, Blomhoff HK, Miura N, Enerback S et al. Mechanisms of FOXC2- and FOXD1-mediated regulation of the RI alpha subunit of cAMP-dependent protein kinase include release of transcriptional repression and activation by protein kinase B alpha and cAMP. J Biol Chem 2002; 277: 22902–22908.

    Article  CAS  Google Scholar 

  31. Masci AM, Galgani M, Cassano S, De Simone S, Gallo A, De Rosa V et al. HIV-1 gp120 induces anergy in naive T lymphocytes through CD4-independent protein kinase-A-mediated signaling. J Leukocyte Biol 2003; 74: 1117–1124.

    Article  CAS  Google Scholar 

  32. Attinger A, Acha-Orbea H, MacDonald HR . Cutting edge: cell autonomous rather than environmental factors control bacterial superantigen-induced T cell anergy in vivo. J Immunol 2000; 165: 1171–1174.

    Article  CAS  Google Scholar 

  33. Yasui D, Miyano M, Cai S, Varga-Weisz P, Kohwi-Shigematsu T . SATB1 targets chromatin remodelling to regulate genes over long distances. Nature 2002; 419: 641–645.

    Article  CAS  Google Scholar 

  34. Lechner O, Lauber J, Franzke A, Sarukhan A, von Boehmer H, Buer J . Fingerprints of anergic T cells. Curr Biol 2001; 11: 587–595.

    Article  CAS  Google Scholar 

  35. Mourtada-Maarabouni M, Kirkham L, Farzaneh F, Williams GT . Regulation of apoptosis by fau revealed by functional expression cloning and antisense expression. Oncogene 2004; 23: 9419–9426.

    Article  CAS  Google Scholar 

  36. Glynne R, Ghandour G, Rayner J, Mack DH, Goodnow CC . B-lymphocyte quiescence, tolerance and activation as viewed by global gene expression profiling on microarrays. Immunol Rev 2000; 176: 216–246.

    Article  CAS  Google Scholar 

  37. Stockinger A, Eger A, Wolf J, Beug H, Foisner R . E-cadherin regulates cell growth by modulating proliferation-dependent beta-catenin transcriptional activity. J Cell Biol 2001; 154: 1185–1196.

    Article  CAS  Google Scholar 

  38. Xu Y, Zhu K, Hong G, Wu W, Baudhuin LM, Xiao Y et al. Sphingosylphosphorylcholine is a ligand for ovarian cancer G-protein-coupled receptor 1. Nat Cell Biol 2000; 2: 261–267.

    Article  CAS  Google Scholar 

  39. Jeon MS, 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: 167–177.

    Article  CAS  Google Scholar 

  40. Sabapathy TK, Hwang LA, Hui KM . Differential effect of staphylococcal enterotoxin B upon the induction of tolerance on peripheral CD4 + V beta 8+ and CD8+V beta 8+ T cells. Cell Immunol 1994; 158: 83–95.

    Article  CAS  Google Scholar 

  41. Sosinowski T, Killeen N, Weiss A . The Src-like adaptor protein downregulates the T cell receptor on CD4+CD8+ thymocytes and regulates positive selection. Immunity 2001; 15: 457–466.

    Article  CAS  Google Scholar 

  42. Sozio MS, Mathis MA, Young JA, Walchli S, Pitcher LA, Wrage PC et al. PTPH1 is a predominant protein-tyrosine phosphatase capable of interacting with and dephosphorylating the T cell receptor zeta subunit. J Biol Chem 2004; 279: 7760–7769.

    Article  CAS  Google Scholar 

  43. Mazerolles F, Barbat C, Trucy M, Kolanus W, Fischer A . Molecular events associated with CD4-mediated down-regulation of LFA-1-dependent adhesion. J Biol Chem 2002; 277: 1276–1283.

    Article  CAS  Google Scholar 

  44. Dillon TJ, Karpitski V, Wetzel SA, Parker DC, Shaw AS, Stork PJ . Ectopic B-Raf expression enhances extracellular signal-regulated kinase (ERK) signaling in T cells and prevents antigen-presenting cell-induced anergy. J Biol Chem 2003; 278: 35940–35949.

    Article  CAS  Google Scholar 

  45. Tsukamoto H, Irie A, Nishimura Y . B-Raf contributes to sustained extracellular signal-regulated kinase activation associated with interleukin-2 production stimulated through the T cell receptor. J Biol Chem 2004; 279: 48457–48465.

    Article  CAS  Google Scholar 

  46. Cone RE, Cochrane R, Lingenheld EG, Clark RB . Elevation of intracellular cyclic AMP induces an anergic-like state in Th1 clones. Cell Immunol 1996; 173: 246–251.

    Article  CAS  Google Scholar 

  47. Ballarin M, Fredholm BB, Ambrosio S, Mahy N . Extracellular levels of adenosine and its metabolites in the striatum of awake rats: inhibition of uptake and metabolism. Acta Physiol Scand 1991; 142: 97–103.

    Article  CAS  Google Scholar 

  48. de Rooij J, Zwartkruis FJ, Verheijen MH, Cool RH, Nijman SM, Wittinghofer A et al. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 1998; 396: 474–477.

    Article  CAS  Google Scholar 

  49. Boussiotis VA, Freeman GJ, Berezovskaya A, Barber DL, Nadler LM . Maintenance of human T cell anergy: blocking of IL-2 gene transcription by activated Rap1. Science 1997; 278: 124–128.

    Article  CAS  Google Scholar 

  50. Bodor J, Bodorova J, Gress RE . Suppression of T cell function: a potential role for transcriptional repressor ICER. J Leukocyte Biol 2000; 67: 774–779.

    Article  CAS  Google Scholar 

  51. Vang T, Torgersen KM, Sundvold V, Saxena M, Levy FO, Skalhegg BS et al. Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. J Exp Med 2001; 193: 497–507.

    Article  CAS  Google Scholar 

  52. Xia D, Stull JT, Kamm KE . Myosin phosphatase targeting subunit 1 affects cell migration by regulating myosin phosphorylation and actin assembly. Exp Cell Res 2005; 304: 506–517.

    Article  CAS  Google Scholar 

  53. Guo X, Stafford LJ, Bryan B, Xia C, Ma W, Wu X et al. A Rac/Cdc42-specific exchange factor, GEFT, induces cell proliferation, transformation, and migration. J Biol Chem 2003; 278: 13207–13215.

    Article  CAS  Google Scholar 

  54. Liu J, Lee KK, Segura-Totten M, Neufeld E, Wilson KL, Gruenbaum Y . MAN1 and emerin have overlapping function(s) essential for chromosome segregation and cell division in Caenorhabditis elegans. Proc Natl Acad Sci USA 2003; 100: 4598–4603.

    Article  CAS  Google Scholar 

  55. Bowerman B . Cell division: timing the machine. Nature 2004; 430: 840–842.

    Article  CAS  Google Scholar 

  56. Tang X, Milyavsky M, Shats I, Erez N, Goldfinger N, Rotter V . Activated p53 suppresses the histone methyltransferase EZH2 gene. Oncogene 2004; 23: 5759–5769.

    Article  CAS  Google Scholar 

  57. Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D . Histone methyltransferase activity associated with a human multiprotein complex containing the enhancer of zeste protein. Genes Dev 2002; 16: 2893–2905.

    Article  CAS  Google Scholar 

  58. Malewicz B, Mukherjee JJ, Crilly KS, Baumann WJ, Kiss Z . Phosphorylation of ethanolamine, methylethanolamine, and dimethylethanolamine by overexpressed ethanolamine kinase in NIH 3T3 cells decreases the co-mitogenic effects of ethanolamines and promotes cell survival. Eur J Biochem 1998; 253: 10–19.

    Article  CAS  Google Scholar 

  59. Ross DA, Kadesch T . Consequences of Notch-mediated induction of Jagged1. Exp Cell Res 2004; 296: 173–182.

    Article  CAS  Google Scholar 

  60. Benson RA, Adamson K, Corsin-Jimenez M, Marley JV, Wahl KA, Lamb JR et al. Notch1 co-localizes with CD4 on activated T cells and Notch signaling is required for IL-10 production. Eur J Immunol 2005; 35: 859–869.

    Article  CAS  Google Scholar 

  61. Roman-Roman S, Shi DL, Stiot V, Hay E, Vayssiere B, Garcia T et al. Murine Frizzled-1 behaves as an antagonist of the canonical Wnt/beta-catenin signaling. J Biol Chem 2004; 279: 5725–5733.

    Article  CAS  Google Scholar 

  62. Halford MM, Armes J, Buchert M, Meskenaite V, Grail D, Hibbs ML et al. Ryk-deficient mice exhibit craniofacial defects associated with perturbed Eph receptor crosstalk. Nat Genet 2000; 25: 414–418.

    Article  CAS  Google Scholar 

  63. Lu W, Yamamoto V, Ortega B, Baltimore D . Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth. Cell 2004; 119: 97–108.

    Article  CAS  Google Scholar 

  64. Julius MH, Simpson E, Herzenberg LA . A rapid method for the isolation of functional thymus-derived murine lymphocytes. Eur J Immunol 1973; 3: 645–649.

    Article  CAS  Google Scholar 

  65. Dozmorov I, Centola M . An associative analysis of gene expression array data. Bioinformatics 2003; 19: 204–211.

    Article  CAS  Google Scholar 

  66. Knowlton N, Dozmorov IM, Centola M . Microarray data analysis toolbox (MDAT): for normalization, adjustment and analysis of gene expression data. Bioinformatics 2004; 20: 3687–3690.

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to Karen Davis and members of the OMRF Flow Cytometry Core Facility for excellent technical support and to Drs Craig Cadwell and Jaya Rajaiya for technical advice. We thank Drs Mark Coggeshall and Linda Thompson for helpful discussions and Kathy Bryant for assistance with bioinformatics. Alison Galatian contributed to these studies as an OMRF Fleming Scholar. This work was supported by grants from the Oklahoma Center for the Advancement of Science and Technology (OCAST; HR02-048) and by the National Institutes of Health (AI48097, K02AI51647 and P20 RR016478-05).

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  1. Arthritis and Immunology Program, Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    S Kurella, J C Yaciuk, I Dozmorov, M B Frank, M Centola & A D Farris

  2. Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    J C Yaciuk & A D Farris

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  1. S Kurella
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Correspondence to A D Farris.

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Kurella, S., Yaciuk, J., Dozmorov, I. et al. Transcriptional modulation of TCR, Notch and Wnt signaling pathways in SEB-anergized CD4+ T cells. Genes Immun 6, 596–608 (2005). https://doi.org/10.1038/sj.gene.6364245

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