Immunologic Research

, 41:137 | Cite as

Negative regulators in homeostasis of naïve peripheral T cells

  • Jaime F. Modiano
  • Lisa D. S. Johnson
  • Donald Bellgrau


It is now apparent that naïve peripheral T cells are a dynamic population where active processes prevent inappropriate activation while supporting survival. The process of thymic education makes naïve peripheral T cells dependent on interactions with self-MHC for survival. However, as these signals can potentially result in inappropriate activation, various non-redundant, intrinsic negative regulatory molecules including Tob, Nfatc2, and Smad3 actively enforce T cell quiescence. Interactions among these pathways are only now coming to light and may include positive or negative crosstalk. In the case of positive crosstalk, self-MHC initiated signals and intrinsic negative regulatory factors may cooperate to dampen T cell activation and sustain peripheral tolerance in a binary fashion (on–off). In the case of negative crosstalk, self-MHC signals may promote survival through partial activation while intrinsic negative regulatory factors act as rheostats to restrain cell cycle entry and prevent T cells from crossing a threshold that would break tolerance.


T cells MHC Sensitization Desensitization Cell cycle Negative regulation Tolerance 



The authors thank Dr. Stephen Jameson for his careful review of the manuscript and helpful suggestions. We regret if meritorious references may have been omitted in the interest of space or brevity. The work was supported by grants R21DK63410, P30CA46934, and R01DK58722 from the National Institutes of Health.


  1. 1.
    Boyman O, Purton JF, Surh CD, Sprent J. Cytokines and T-cell homeostasis. Curr Opin Immunol. 2007;19:320–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Cho JH, Boyman O, Kim HO, Hahm B, Rubinstein MP, Ramsey C, et al. An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2. J Exp Med. 2007;204:1787–801.PubMedCrossRefGoogle Scholar
  3. 3.
    Kamimura D, Bevan MJ. Naive CD8+ T cells differentiate into protective memory-like cells after IL-2 anti IL-2 complex treatment in vivo. J Exp Med. 2007;204:1803–12.PubMedCrossRefGoogle Scholar
  4. 4.
    Sandau MM, Winstead CJ, Jameson SC. IL-15 is required for sustained lymphopenia-driven proliferation and accumulation of CD8 T cells. J Immunol. 2007;179:120–5.PubMedGoogle Scholar
  5. 5.
    Goldrath AW, Bogatzki LY, Bevan MJ. Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J Exp Med. 2000;192:557–64.PubMedCrossRefGoogle Scholar
  6. 6.
    Kieper WC, Jameson SC. Homeostatic expansion and phenotypic conversion of naive T cells in response to self peptide/MHC ligands. Proc Natl Acad Sci USA. 1999;96:13306–11.PubMedCrossRefGoogle Scholar
  7. 7.
    Bhandoola A, Tai X, Eckhaus M, Auchincloss H, Mason K, Rubin SA, et al. Peripheral expression of self-MHC-II influences the reactivity and self-tolerance of mature CD4(+) T cells: evidence from a lymphopenic T cell model. Immunity. 2002;17:425–36.PubMedCrossRefGoogle Scholar
  8. 8.
    Goldrath AW, Luckey CJ, Park R, Benoist C, Mathis D. The molecular program induced in T cells undergoing homeostatic proliferation. Proc Natl Acad Sci USA. 2004;101:16885–90.PubMedCrossRefGoogle Scholar
  9. 9.
    Hamilton SE, Wolkers MC, Schoenberger SP, Jameson SC. The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+ T cells. Nat Immunol. 2006;7:475–81.PubMedCrossRefGoogle Scholar
  10. 10.
    Troy AE, Shen H. Cutting edge: homeostatic proliferation of peripheral T lymphocytes is regulated by clonal competition. J Immunol. 2003;170:672–6.PubMedGoogle Scholar
  11. 11.
    Min B, Foucras G, Meier-Schellersheim M, Paul WE. Spontaneous proliferation, a response of naive CD4 T cells determined by the diversity of the memory cell repertoire. Proc Natl Acad Sci USA. 2004;101:3874–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Tan JT, Ernst B, Kieper WC, LeRoy E, Sprent J, Surh CD. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J Exp Med. 2002;195:1523–32.PubMedCrossRefGoogle Scholar
  13. 13.
    Shen S, Ding Y, Tadokoro CE, Olivares-Villagomez D, Camps-Ramirez M, Curotto de Lafaille MA, et al. Control of homeostatic proliferation by regulatory T cells. J Clin Invest. 2005;115:3517–26.PubMedCrossRefGoogle Scholar
  14. 14.
    Surh CD, Boyman O, Purton JF, Sprent J. Homeostasis of memory T cells. Immunol Rev. 2006;211:154–63.PubMedCrossRefGoogle Scholar
  15. 15.
    Li O, Chang X, Zhang H, Kocak E, Ding C, Zheng P, et al. Massive and destructive T cell response to homeostatic cue in CD24-deficient lymphopenic hosts. J Exp Med. 2006;203:1713–20.PubMedCrossRefGoogle Scholar
  16. 16.
    Nesic D, Vukmanovic S. MHC class I is required for peripheral accumulation of CD8+ thymic emigrants. J Immunol. 1998;160:3705–12.PubMedGoogle Scholar
  17. 17.
    Murali-Krishna K, Lau LL, Sambhara S, Lemonnier F, Altman J, Ahmed R. Persistence of memory CD8 T cells in MHC class I-deficient mice. Science. 1999;286:1377–81.PubMedCrossRefGoogle Scholar
  18. 18.
    Boursalian TE, Bottomly K. Survival of naive CD4 T cells: roles of restricting versus selecting MHC class II and cytokine milieu. J Immunol. 1999;162:3795–801.PubMedGoogle Scholar
  19. 19.
    Viret C, Janeway CA Jr. MHC and T cell development. Rev Immunogenet. 1999;1:91–104.PubMedGoogle Scholar
  20. 20.
    Witherden D, van Oers N, Waltzinger C, Weiss A, Benoist C, Mathis D. Tetracycline-controllable selection of CD4(+) T cells: half-life and survival signals in the absence of major histocompatibility complex class II molecules. J Exp Med. 2000;191:355–64.PubMedCrossRefGoogle Scholar
  21. 21.
    Martin B, Bourgeois C, Dautigny N, Lucas B. On the role of MHC class II molecules in the survival and lymphopenia-induced proliferation of peripheral CD4+ T cells. Proc Natl Acad Sci USA. 2003;100:6021–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Dorfman JR, Germain RN. MHC-dependent survival of naive T cells? A complicated answer to a simple question. Microbes Infect. 2002;4:547–54.PubMedCrossRefGoogle Scholar
  23. 23.
    Jabbari A, Harty JT. Cutting edge: differential self-peptide/MHC requirement for maintaining CD8 T cell function versus homeostatic proliferation. J Immunol. 2005;175:4829–33.PubMedGoogle Scholar
  24. 24.
    Markiewicz MA, Brown I, Gajewski TF. Death of peripheral CD8+ T cells in the absence of MHC class I is Fas-dependent and not blocked by Bcl-xL. Eur J Immunol. 2003;33:2917–26.PubMedCrossRefGoogle Scholar
  25. 25.
    Tanchot C, Lemonnier FA, Perarnau B, Freitas AA, Rocha B. Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science. 1997;276:2057–62.PubMedCrossRefGoogle Scholar
  26. 26.
    Grandjean I, Duban L, Bonney EA, Corcuff E, Di Santo JP, Matzinger P, et al. Are major histocompatibility complex molecules involved in the survival of naive CD4+ T cells? J Exp Med. 2003;198:1089–102.PubMedCrossRefGoogle Scholar
  27. 27.
    Grossman Z, Paul WE. Adaptive cellular interactions in the immune system: the tunable activation threshold and the significance of subthreshold responses. Proc Natl Acad Sci USA. 1992;89:10365–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Kassiotis G, Zamoyska R, Stockinger B. Involvement of avidity for major histocompatibility complex in homeostasis of naive and memory T cells. J Exp Med. 2003;197:1007–16.PubMedCrossRefGoogle Scholar
  29. 29.
    Kieper WC, Burghardt JT, Surh CD. A role for TCR affinity in regulating naive T cell homeostasis. J Immunol. 2004;172:40–4.PubMedGoogle Scholar
  30. 30.
    Stefanova I, Dorfman JR, Germain RN. Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature. 2002;420:429–34.PubMedCrossRefGoogle Scholar
  31. 31.
    Fischer UB, Jacovetty EL, Medeiros RB, Goudy BD, Zell T, Swanson JB, et al. MHC class II deprivation impairs CD4 T cell motility and responsiveness to antigen-bearing dendritic cells in vivo. Proc Natl Acad Sci USA. 2007;104:7181–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Dummer W, Niethammer AG, Baccala R, Lawson BR, Wagner N, Reisfeld RA, et al. T cell homeostatic proliferation elicits effective antitumor autoimmunity. J Clin Invest. 2002;110:185–92.PubMedGoogle Scholar
  33. 33.
    Hu HM, Poehlein CH, Urba WJ, Fox BA. Development of antitumor immune responses in reconstituted lymphopenic hosts. Cancer Res. 2002;62:3914–9.PubMedGoogle Scholar
  34. 34.
    Marleau AM, Sarvetnick N. T cell homeostasis in tolerance and immunity. J Leukoc Biol. 2005;78:575–84.PubMedCrossRefGoogle Scholar
  35. 35.
    Brown IE, Blank C, Kline J, Kacha AK, Gajewski TF. Homeostatic proliferation as an isolated variable reverses CD8+ T cell anergy and promotes tumor rejection. J Immunol. 2006;177:4521–9.PubMedGoogle Scholar
  36. 36.
    Bracci L, Moschella F, Sestili P, La Sorsa V, Valentini M, Canini I, et al. Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin Cancer Res. 2007;13:644–53.PubMedCrossRefGoogle Scholar
  37. 37.
    Maeda Y, Tawara I, Teshima T, Liu C, Hashimoto D, Matsuoka K, et al. Lymphopenia-induced proliferation of donor T cells reduces their capacity for causing acute graft-versus-host disease. Exp Hematol. 2007;35:274–86.PubMedCrossRefGoogle Scholar
  38. 38.
    Anderson BE, McNiff J, Yan J, Doyle H, Mamula M, Shlomchik MJ, et al. Memory CD4+ T cells do not induce graft-versus-host disease. J Clin Invest. 2003;112:101–8.PubMedGoogle Scholar
  39. 39.
    Chen BJ, Cui X, Sempowski GD, Liu C, Chao NJ. Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease. Blood. 2004;103:1534–41.PubMedCrossRefGoogle Scholar
  40. 40.
    Chen BJ, Deoliveira D, Cui X, Le NT, Son J, Whitesides JF, et al. Inability of memory T cells to induce graft-versus-host disease is a result of an abortive alloresponse. Blood. 2007;109:3115–23.PubMedGoogle Scholar
  41. 41.
    Boise LH, Thompson CB. Hierarchical control of lymphocyte survival. Science. 1996;274:67–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Lang JA, Kominski D, Bellgrau D, Scheinman RI. Partial activation precedes apoptotic death in T cells harboring an IAN gene mutation. Eur J Immunol. 2004;34:2396–406.PubMedCrossRefGoogle Scholar
  43. 43.
    Baksh S, Widlund HR, Frazer-Abel AA, Du J, Fosmire S, Fisher DE, et al. NFATc2-mediated repression of cyclin-dependent kinase 4 expression. Mol Cell. 2002;10:1071–81.PubMedCrossRefGoogle Scholar
  44. 44.
    Frazer-Abel AA, Baksh S, Fosmire SP, Willis D, Pierce AM, Meylemans H, et al. Nicotine activates NFATc2 and prevents cell cycle entry in T cells. J Pharmacol Exp Ther. 2004;311:758–69.PubMedCrossRefGoogle Scholar
  45. 45.
    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;5:255–65.PubMedCrossRefGoogle Scholar
  46. 46.
    Macian F, Garcia-Cozar F, Im SH, Horton HF, Byrne MC, Rao A. Transcriptional mechanisms underlying lymphocyte tolerance. Cell. 2002;109:719–31.PubMedCrossRefGoogle Scholar
  47. 47.
    Yusuf I, Fruman DA. Regulation of quiescence in lymphocytes. Trends Immunol. 2003;24:380–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Frisch SM. Evidence for a function of death-receptor-related, death-domain- containing proteins in anoikis. Curr Biol. 1999;9:1047–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Frisch SM, Screaton RA. Anoikis mechanisms. Curr Opin Cell Biol. 2001;13:555–62.PubMedCrossRefGoogle Scholar
  50. 50.
    Modiano JF, Ritt MG, Wojcieszyn J, Smith R 3rd. Growth arrest of melanoma cells is differentially regulated by contact inhibition and serum deprivation. DNA Cell Biol. 1999;18:357–67.PubMedCrossRefGoogle Scholar
  51. 51.
    Kupfer R, Lang J, Williams-Skipp C, Nelson M, Bellgrau D, Scheinman RI. Loss of a gimap/ian gene leads to activation of NF-kappaB through a MAPK-dependent pathway. Mol Immunol. 2007;44:479–87.PubMedCrossRefGoogle Scholar
  52. 52.
    Tzachanis D, Freeman GJ, Hirano N, van Puijenbroek AA, Delfs MW, Berezovskaya A, et al. Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nat Immunol. 2001;2:1174–82.PubMedCrossRefGoogle Scholar
  53. 53.
    Letterio JJ. TGF-β signaling in T cells: roles in lymphoid and epithelial neoplasia. Oncogene. 2005;24:5701–12.PubMedCrossRefGoogle Scholar
  54. 54.
    Li L, Iwamoto Y, Berezovskaya A, Boussiotis VA. A pathway regulated by cell cycle inhibitor p27Kip1 and checkpoint inhibitor Smad3 is involved in the induction of T cell tolerance. Nat Immunol. 2006;7:1157–65.PubMedCrossRefGoogle Scholar
  55. 55.
    Classen S, Zander T, Eggle D, Chemnitz JM, Brors B, Buchmann I, et al. Human resting CD4+ T cells are constitutively inhibited by TGF β under steady-state conditions. J Immunol. 2007;178:6931–40.PubMedGoogle Scholar
  56. 56.
    McKarns SC, Schwartz RH, Kaminski NE. Smad3 is essential for TGF-β 1 to suppress IL-2 production and TCR-induced proliferation, but not IL-2-induced proliferation. J Immunol. 2004;172:4275–84.PubMedGoogle Scholar
  57. 57.
    Yang X, Letterio JJ, Lechleider RJ, Chen L, Hayman R, Gu H, et al. Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-β. EMBO J. 1999;18:1280–91.PubMedCrossRefGoogle Scholar
  58. 58.
    Nitta T, Takahama Y. The lymphocyte guard-IANs: regulation of lymphocyte survival by IAN/GIMAP family proteins. Trends Immunol. 2007;28:58–65.PubMedCrossRefGoogle Scholar
  59. 59.
    MacMurray AJ, Moralejo DH, Kwitek AE, Rutledge EA, Van Yserloo B, Gohlke P, et al. Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (Ian)-related gene. Genome Res. 2002;12:1029–39.PubMedCrossRefGoogle Scholar
  60. 60.
    Nitta T, Nasreen M, Seike T, Goji A, Ohigashi I, Miyazaki T, et al. IAN family critically regulates survival and development of T lymphocytes. PLoS Biol. 2006;4:e103.PubMedCrossRefGoogle Scholar
  61. 61.
    Keita M, Leblanc C, Andrews D, Ramanathan S. GIMAP5 regulates mitochondrial integrity from a distinct subcellular compartment. Biochem Biophys Res Commun. 2007;361:481–6.PubMedCrossRefGoogle Scholar
  62. 62.
    Zadeh HH, Greiner DL, Wu DY, Tausche F, Goldschneider I. Abnormalities in the export and fate of recent thymic emigrants in diabetes-prone BB/W rats. Autoimmunity. 1996;24:35–46.PubMedCrossRefGoogle Scholar
  63. 63.
    Ramanathan S, Norwich K, Poussier P. Antigen activation rescues recent thymic emigrants from programmed cell death in the BB rat. J Immunol. 1998;160:5757–64.PubMedGoogle Scholar
  64. 64.
    Moore JK, Scheinman RI, Bellgrau D. The identification of a novel T cell activation state controlled by a diabetogenic gene. J Immunol. 2001;166:241–8.PubMedGoogle Scholar
  65. 65.
    Jia S, Meng A. Tob genes in development and homeostasis. Dev Dyn. 2007;236:913–21.PubMedCrossRefGoogle Scholar
  66. 66.
    Kawamura-Tsuzuku J, Suzuki T, Yoshida Y, Yamamoto T. Nuclear localization of Tob is important for regulation of its antiproliferative activity. Oncogene. 2004;23:6630–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Maekawa M, Nishida E, Tanoue T. Identification of the anti-proliferative protein Tob as a MAPK substrate. J Biol Chem. 2002;277:37783–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Suzuki T, Kawamura-Tsuzuku J, Ajima R, Nakamura T, Yoshida Y, Yamamoto T. Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation. Genes Dev. 2002;16:1356–70.PubMedCrossRefGoogle Scholar
  69. 69.
    Hiramatsu Y, Kitagawa K, Suzuki T, Uchida C, Hattori T, Kikuchi H, et al. Degradation of Tob1 mediated by SCFSkp2-dependent ubiquitination. Cancer Res. 2006;66:8477–83.PubMedCrossRefGoogle Scholar
  70. 70.
    Yamashiro H, Odani Y, Hozumi N, Nakano N. Hierarchical signaling thresholds determine the fates of naive T cells: partial priming leads nai;ve T cells to unresponsiveness. Biochem Biophys Res Commun. 2002;299:148–54.PubMedCrossRefGoogle Scholar
  71. 71.
    Kiani A, Rao A, Aramburu J. Manipulating immune responses with immunosuppressive agents that target NFAT. Immunity. 2000;12:359–72.PubMedCrossRefGoogle Scholar
  72. 72.
    Xanthoudakis S, Viola JP, Shaw KT, Luo C, Wallace JD, Bozza PT, et al. An enhanced immune response in mice lacking the transcription factor NFAT1. Science. 1996;272:892–5.PubMedCrossRefGoogle Scholar
  73. 73.
    Sundrud MS, Rao A. New twists of T cell fate: control of T cell activation and tolerance by TGF-β and NFAT. Curr Opin Immunol. 2007;19:287–93.PubMedCrossRefGoogle Scholar
  74. 74.
    Derynck R, Zhang Y, Feng X-H. Transcriptional activators of TGF-[β] responses: smads. Cell. 1998;95:737–40.PubMedCrossRefGoogle Scholar
  75. 75.
    Massague J, Weinberg RA. Negative regulators of growth. Curr Opin Genet Dev. 1992;2:28–32.PubMedCrossRefGoogle Scholar
  76. 76.
    Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, et al. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-β and contact inhibition to cell cycle arrest. Genes Dev. 1994;8:9–22.PubMedCrossRefGoogle Scholar
  77. 77.
    Quelle DE, Ashmun RA, Hannon GJ, Rehberger PA, Trono D, Richter KH, et al. Cloning and characterization of murine p16INK4a and p15INK4b genes. Oncogene. 1995;11:635–45.PubMedGoogle Scholar
  78. 78.
    Kehrl JH, Wakefield LM, Roberts AB, Jakowlew S, Alvarez-Mon M, Derynck R, Sporn MB, et al. Production of transforming growth factor β by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med. 1986;163:1037–50.PubMedCrossRefGoogle Scholar
  79. 79.
    McKarns SC, Schwartz RH. Distinct effects of TGF-β 1 on CD4+ and CD8+ T cell survival, division, and IL-2 production: a role for T cell intrinsic Smad3. J Immunol. 2005;174:2071–83.PubMedGoogle Scholar
  80. 80.
    Ranges GE, Figari IS, Espevik T, Palladino MA Jr. Inhibition of cytotoxic T cell development by transforming growth factor β and reversal by recombinant tumor necrosis factor alpha. J Exp Med. 1987;166:991–8.PubMedCrossRefGoogle Scholar
  81. 81.
    Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-[β] induces development of the TH17 lineage. Nature. 2006;441:231–4.PubMedCrossRefGoogle Scholar
  82. 82.
    Marie JC, Letterio JJ, Gavin M, Rudensky AY. TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med. 2005;201:1061–7.PubMedCrossRefGoogle Scholar
  83. 83.
    Wolfraim LA, Walz TM, James Z, Fernandez T, Letterio JJ. p21Cip1 and p27Kip1 act in synergy to alter the sensitivity of naive T cells to TGF-β-mediated G1 arrest through modulation of IL-2 responsiveness. J Immunol. 2004;173:3093–102.PubMedGoogle Scholar
  84. 84.
    Modiano JF, Mayor J, Ball C, Fuentes MK, Linthicum DS. Cdk4 expression and activity are required for cytokine responsiveness in T cells. J Immunol. 2000;165:6693–702.PubMedGoogle Scholar
  85. 85.
    Matsuura I, Denissova NG, Wang G, He D, Long J, Liu F. Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature. 2004;430:226–31.PubMedCrossRefGoogle Scholar
  86. 86.
    Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, et al. Transforming growth factor β 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA. 1993;90:770–4.PubMedCrossRefGoogle Scholar
  87. 87.
    Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, et al. Targeted disruption of the mouse transforming growth factor-β 1 gene results in multifocal inflammatory disease. Nature. 1992;359:693–9.PubMedCrossRefGoogle Scholar
  88. 88.
    Diebold RJ, Eis MJ, Yin M, Ormsby I, Boivin GP, Darrow BJ, et al. Early-onset multifocal inflammation in the transforming growth factor β 1-null mouse is lymphocyte mediated. Proc Natl Acad Sci USA. 1995;92:12215–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Kobayashi S, Yoshida K, Ward JM, Letterio JJ, Longenecker G, et al. β2-microglobulin-deficient background ameliorates lethal phenotype of the TGF-β1 null mouse. J Immunol. 1999;163:4013–9.PubMedGoogle Scholar
  90. 90.
    Leveen P, Carlsen M, Makowska A, Oddsson S, Larsson J, Goumans MJ, et al. TGF-β type II receptor-deficient thymocytes develop normally but demonstrate increased CD8+ proliferation in vivo. Blood. 2005;106:4234–40.PubMedCrossRefGoogle Scholar
  91. 91.
    Li MO, Sanjabi S, Flavell RA. Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity. 2006;25:455–71.PubMedCrossRefGoogle Scholar
  92. 92.
    Lucas PJ, Kim SJ, Melby SJ, Gress RE. Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor β II receptor. J Exp Med. 2000;191:1187–96.PubMedCrossRefGoogle Scholar
  93. 93.
    Marie JC, Liggitt D, Rudensky AY. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-β receptor. Immunity. 2006;25:441–54.PubMedCrossRefGoogle Scholar
  94. 94.
    Gorelik L, Flavell RA. Abrogation of TGF β signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity. 2000;12:171–81.PubMedCrossRefGoogle Scholar
  95. 95.
    Lucas PJ, Kim SJ, Mackall CL, Telford WG, Chu YW, Hakim FT, et al. Dysregulation of IL-15-mediated T-cell homeostasis in TGF-β dominant-negative receptor transgenic mice. Blood. 2006;108:2789–95.PubMedCrossRefGoogle Scholar
  96. 96.
    Warner BJ, Blain SW, Seoane J, Massague J. Myc downregulation by transforming growth factor β required for activation of the p15Ink4b G1 arrest pathway. Mol Cell Biol. 1999;19:5913–22.PubMedGoogle Scholar
  97. 97.
    Bianchi T, Gasser S, Trumpp A, MacDonald HR. c-Myc acts downstream of IL-15 in the regulation of memory CD8 T-cell homeostasis. Blood. 2006;107:3992–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Campbell JD, Cook G, Robertson SE, Fraser A, Boyd KS, Gracie JA, et al. Suppression of IL-2-induced T cell proliferation and phosphorylation of STAT3 and STAT5 by tumor-derived TGF β is reversed by IL-15. J Immunol. 2001;167:553–61.PubMedGoogle Scholar
  99. 99.
    Koehler H, Kofler D, Hombach A, Abken H. CD28 costimulation overcomes transforming growth factor-β-mediated repression of proliferation of redirected human CD4+ and CD8+ T cells in an antitumor cell attack. Cancer Res. 2007;67:2265–73.PubMedCrossRefGoogle Scholar
  100. 100.
    Sung JL, Lin JT, Gorham JD. CD28 co-stimulation regulates the effect of transforming growth factor-β1 on the proliferation of naive CD4+ T cells. Int Immunopharmacol. 2003;3:233–45.PubMedCrossRefGoogle Scholar
  101. 101.
    Ahmadzadeh M, Rosenberg SA. TGF-β 1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J Immunol. 2005;174:5215–23.PubMedGoogle Scholar
  102. 102.
    Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-β signaling in T cells. Nat Med. 2001;7:1118–22.PubMedCrossRefGoogle Scholar
  103. 103.
    Zhang Q, Yang XJ, Kundu SD, Pins M, Javonovic B, Meyer R, et al. Blockade of transforming growth factor-β signaling in tumor-reactive CD8+ T cells activates the antitumor immune response cycle. Mol Cancer Ther. 2006;5:1733–43.PubMedCrossRefGoogle Scholar
  104. 104.
    Fahlen L, Read S, Gorelik L, Hurst SD, Coffman RL, Flavell RA, et al. T cells that cannot respond to TGF-β escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med. 2005;201:737–46.PubMedCrossRefGoogle Scholar
  105. 105.
    Kerstan A, Hunig T. Cutting edge: distinct TCR- and CD28-derived signals regulate CD95L, Bcl-xL, and the survival of primary T cells. J Immunol. 2004;172:1341–5.PubMedGoogle Scholar
  106. 106.
    Rowell EA, Walsh MC, Wells AD. 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.PubMedGoogle Scholar
  107. 107.
    Wolfraim LA, Letterio JJ. Cutting edge: p27Kip1 deficiency reduces the requirement for CD28-mediated costimulation in naive CD8+ but not CD4+ T lymphocytes. J Immunol. 2005;174:2481–4.PubMedGoogle Scholar
  108. 108.
    Bettini M, Xi H, Kersh GJ. T cell stimulation in the absence of exogenous antigen: a T cell signal is induced by both MHC-dependent and -independent mechanisms. Eur J Immunol. 2003;33:3109–16.PubMedCrossRefGoogle Scholar
  109. 109.
    Berridge MJ. Lymphocyte activation in health and disease. Crit Rev Immunol. 1997;17:155–78.PubMedGoogle Scholar
  110. 110.
    Janeway CA Jr, Bottomly K. Signals and signs for lymphocyte responses. Cell. 1994;76:275–85.PubMedCrossRefGoogle Scholar
  111. 111.
    Shahinian A, Pfeffer K, Lee KP, Kundig TM, Kishihara K, Wakeham A, et al. Differential T cell costimulatory requirements in CD28-deficient mice. Science. 1993;261:609–12.PubMedCrossRefGoogle Scholar
  112. 112.
    Kane LP, Weiss A. The PI-3 kinase/Akt pathway and T cell activation: pleiotropic pathways downstream of PIP3. Immunol Rev. 2003;192:7–20.PubMedCrossRefGoogle Scholar
  113. 113.
    Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol. 2003;3:317–30.PubMedCrossRefGoogle Scholar
  114. 114.
    Okkenhaug K, Vanhaesebroeck B. PI3K-signalling in B- and T-cells: insights from gene-targeted mice. Biochem Soc Trans. 2003;31:270–4.PubMedCrossRefGoogle Scholar
  115. 115.
    Altman A, Villalba M. Protein kinase C-theta (PKCtheta): it’s all about location, location, location. Immunol Rev. 2003;192:53–63.PubMedCrossRefGoogle Scholar
  116. 116.
    Jones RG, Elford AR, Parsons MJ, Wu L, Krawczyk CM, Yeh WC, et al. CD28-dependent activation of protein kinase B/Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assembly. J Exp Med. 2002;196:335–48.PubMedCrossRefGoogle Scholar
  117. 117.
    Sulis ML, Parsons R. PTEN: from pathology to biology. Trends Cell Biol. 2003;13:478–83.PubMedCrossRefGoogle Scholar
  118. 118.
    Di Cristofano A, Kotsi P, Peng YF, Cordon-Cardo C, Elkon KB, Pandolfi PP. Impaired Fas response and autoimmunity in Pten+/− mice. Science. 1999;285:2122–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Jaime F. Modiano
    • 1
    • 2
    • 3
    • 4
    • 5
  • Lisa D. S. Johnson
    • 5
  • Donald Bellgrau
    • 1
    • 2
  1. 1.Integrated Department of ImmunologyUniversity of Colorado DenverDenverUSA
  2. 2.University of Colorado Cancer CenterDenverUSA
  3. 3.Department of Veterinary Clinical SciencesUniversity of MinnesotaSt. PaulUSA
  4. 4.University of Minnesota Cancer CenterMinneapolisUSA
  5. 5.Graduate Program on Microbiology, Cancer Biology and ImmunologyUniversity of MinnesotaMinneapolisUSA

Personalised recommendations