The Role of IL-2 in the Development and Peripheral Homeostasis of Naturally Occurring CD4+CD25+Foxp3+ Regulatory T Cells

  • Allison L. Bayer
  • Thomas R. Malek


Naturally occurring CD4+CD25+Foxp3+ regulatory T cells (Treg) actively suppress autoreactive T cells that escape negative selection in the thymus, preventing a wide variety of autoimmune diseases. Along with Foxp3, the high affinity IL-2R represents one of the better characterized molecules of Treg cells. Current data support models where the IL-2/IL-2R interaction, primarily through STAT5 activation, controls Treg cell development in the thymus and their growth and maintenance in peripheral immune tissues. The recent link between IL-2R signaling and upregulation of Foxp3 also raises the possibility that IL-2 is important for Treg cell suppressive function. Other important issues concern the cellular source of IL-2 and novel aspects that potentially regulate and limit IL-2 to Treg cells. Although IL-2 is essential, other cytokines within and outside the γc family likely contribute to Treg cell production.


Treg Cell Foxp3 Expression Janus Activate Kinase Peripheral Treg Cell Peripheral Homeostasis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Our work is support by grants from the NIH and JDRF.


  1. 1.
    Sakaguchi, S., N. Sakaguchi, M. Asano, M. Itoh, and M. Toda. 1995. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164.PubMedGoogle Scholar
  2. 2.
    Malek, T.R., and A.L. Bayer. 2004. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol 4:665–674.PubMedCrossRefGoogle Scholar
  3. 3.
    Shevach, E.M. 2000. Suppressor T cells: rebirth, function and homeostasis. Curr Biol 10:R572–575.PubMedCrossRefGoogle Scholar
  4. 4.
    Sadlack, B., J. Lohler, H. Schorle, G. Klebb, H. Haber, E. Sickel, R.J. Noelle, and I. Horak. 1995. Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur J Immunol 25:3053–3059.PubMedCrossRefGoogle Scholar
  5. 5.
    Sadlack, B., H. Merz, H. Schorle, A. Schimpl, A.C. Feller, and I. Horak. 1993. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75:253–261.PubMedCrossRefGoogle Scholar
  6. 6.
    Papiernik, M., M.L. de Moraes, C. Pontoux, F. Vasseur, and C. Penit. 1998. Regulatory CD4 T cells: expression of IL-2Rα chain, resistance to clonal deletion and IL-2 dependency. Int Immunol 10:371–378.PubMedCrossRefGoogle Scholar
  7. 7.
    Suzuki, H., T.M. Kundig, C. Furlonger, A. Wakeham, E. Timms, T. Matsuyama, R. Schmits, J.J. Simard, P.S. Ohashi, H. Griesser et al. 1995. Deregulated T cell activation and autoimmunity in mice lacking interleulin 2 receptor β. Science 268:1472–1476.PubMedCrossRefGoogle Scholar
  8. 8.
    Willerford, D.M., J. Chen, J.A. Ferry, L. Davidson, A. Ma, and F.W. Alt. 1995. Interleukin-2 receptor α-chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3:521–530.PubMedCrossRefGoogle Scholar
  9. 9.
    Kramer, S., A. Schimpl, and T. Hunig. 1995. Immunopathology of interleukin (IL) 2-deficient mice: thymus dependence and suppression by thymus-dependent cells with an intact IL-2 gene. J Exp Med 182:1769–1776.PubMedCrossRefGoogle Scholar
  10. 10.
    Malek, T.R., A. Yu, V. Vincek, P. Scibelli, and L. Kong. 2002. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17:167–178.PubMedCrossRefGoogle Scholar
  11. 11.
    Kneitz, B., T. Herrmann, S. Yonehara, and A. Schimpl. 1995. Normal clonal expansion but impaired Fas-mediated cell death and anergy induction in interleukin-2-deficient mice. Eur J Immunol 25:2572–2577.PubMedCrossRefGoogle Scholar
  12. 12.
    Lenardo, M.J. 1991. Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature 353:858–861.PubMedCrossRefGoogle Scholar
  13. 13.
    van Parijs, L., V.L. Perez, and A.K. Abbas. 1998. Mechanisms of peripheral T cell tolerance. Novartis Found Symp 215:5–14; discussion 14–20, 33–40.PubMedGoogle Scholar
  14. 14.
    Malek, T.R., B.O. Porter, E.K. Codias, P. Scibelli, and A. Yu. 2000. Normal lymphoid homeostasis and lack of lethal autoimmunity in mice containing mature T cells with severely impaired IL-2 receptors. J Immunol 164:2905–2914.PubMedGoogle Scholar
  15. 15.
    Suzuki, H., Y.W. Zhou, M. Kato, T.W. Mak, and I. Nakashima. 1999. Normal regulatory α/β T cells effectively eliminate abnormally activated T cells lacking the interleukin 2 receptor β in vivo. J Exp Med 190:1561–1572.PubMedCrossRefGoogle Scholar
  16. 16.
    Wolf, M., A. Schimpl, and T. Hunig. 2001. Control of T cell hyperactivation in IL-2-deficient mice by CD4+CD25 and CD4+CD25+ T cells: evidence for two distinct regulatory mechanisms. Eur J Immunol 31:1637–1645.PubMedCrossRefGoogle Scholar
  17. 17.
    Klebb, G., I.B. Autenrieth, H. Haber, E. Gillert, B. Sadlack, K.A. Smith, and I. Horak. 1996. Interleukin-2 is indispensable for development of immunological self-tolerance. Clin Immunol Immunopathol 81:282–286.PubMedCrossRefGoogle Scholar
  18. 18.
    Bayer, A., A. Yu, and T. Malek. 2007. Function of the IL-2R for thymic and peripheral CD4+CD25+ Foxp3+ T regulatory cells. J Immunol 178:4062–4071.Google Scholar
  19. 19.
    Almeida, A.R., N. Legrand, M. Papiernik, and A.A. Freitas. 2002. Homeostasis of peripheral CD4+ T cells: IL-2Rα and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J Immunol 169:4850–4860.PubMedGoogle Scholar
  20. 20.
    Furtado, G.C., M.A. Curotto de Lafaille, N. Kutchukhidze, and J.J. Lafaille. 2002. Interleukin 2 signaling is required for CD4+ regulatory T cell function. J Exp Med 196: 851–857.PubMedCrossRefGoogle Scholar
  21. 21.
    Sharfe, N., H.K. Dadi, M. Shahar, and C.M. Roifman. 1997. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci USA 94:3168–3171.PubMedCrossRefGoogle Scholar
  22. 22.
    Fontenot, J.D., M.A. Gavin, and A.Y. Rudensky. 2003. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336.PubMedCrossRefGoogle Scholar
  23. 23.
    Hori, S., T. Nomura, and S. Sakaguchi. 2003. Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061.PubMedCrossRefGoogle Scholar
  24. 24.
    Khattri, R., T. Cox, S.A. Yasayko, and F. Ramsdell. 2003. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4:337–342.PubMedCrossRefGoogle Scholar
  25. 25.
    Fontenot, J.D., J.L. Dooley, A.G. Farr, and A.Y. Rudensky. 2005. Developmental regulation of Foxp3 expression during ontogeny. J Exp Med 202:901–906.PubMedCrossRefGoogle Scholar
  26. 26.
    Nelson, B.H. 2002. Interleukin-2 signaling and the maintenance of self-tolerance. Curr Dir Autoimmun 5:92–112.PubMedCrossRefGoogle Scholar
  27. 27.
    Antov, A., L. Yang, M. Vig, D. Baltimore, and L. Van Parijs. 2003. Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance. J Immunol 171:3435–3441.PubMedGoogle Scholar
  28. 28.
    Burchill, M.A., C.A. Goetz, M. Prlic, J.J. O'Neil, I.R. Harmon, S.J. Bensinger, L.A. Turka, P. Brennan, S.C. Jameson, and M.A. Farrar. 2003. Distinct effects of STAT5 activation on CD4+ and CD8+ T cell homeostasis: development of CD4+CD25+ regulatory T cells versus CD8+ memory T cells. J Immunol 171:5853–5864.PubMedGoogle Scholar
  29. 29.
    Burchill, M.A., J. Yang, C. Vogtenhuber, B.R. Blazar, and M.A. Farrar. 2007. IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol 178:280–290.PubMedGoogle Scholar
  30. 30.
    Snow, J.W., N. Abraham, M.C. Ma, B.G. Herndier, A.W. Pastuszak, and M.A. Goldsmith. 2003. Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5B-deficient mice. J Immunol 171:5042–5050.PubMedGoogle Scholar
  31. 31.
    Fontenot, J.D., J.P. Rasmussen, M.A. Gavin, and A.Y. Rudensky. 2005. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6:1142–1151.PubMedCrossRefGoogle Scholar
  32. 32.
    Cohen, A.C., K.C. Nadeau, W. Tu, V. Hwa, K. Dionis, L. Bezrodnik, A. Teper, M. Gaillard, J. Heinrich, A.M. Krensky, R.G. Rosenfeld, and D.B. Lewis. 2006. Cutting edge: decreased accumulation and regulatory function of CD4+ CD25(high) T cells in human STAT5b deficiency. J Immunol 177:2770–2774.PubMedGoogle Scholar
  33. 33.
    Zorn, E., E.A. Nelson, M. Mohseni, F. Porcheray, H. Kim, D. Litsa, R. Bellucci, E. Raderschall, C. Canning, R.J. Soiffer, D.A. Frank, and J. Ritz. 2006. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108:1571–1579.PubMedCrossRefGoogle Scholar
  34. 34.
    Murawski, M.R., S.A. Litherland, M.J. Clare-Salzler, and A. Davoodi-Semiromi. 2006. Upregulation of Foxp3 expression in mouse and human Treg is IL-2/STAT5 dependent: implications for the NOD STAT5B mutation in diabetes pathogenesis. Ann N Y Acad Sci 1079: 198–204.PubMedCrossRefGoogle Scholar
  35. 35.
    Sugimoto, N., T. Oida, K. Hirota, K. Nakamura, T. Nomura, T. Uchiyama, and S. Sakaguchi. 2006. Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis. Int Immunol 18:1197–1209.PubMedCrossRefGoogle Scholar
  36. 36.
    Bensinger, S.J., P.T. Walsh, J. Zhang, M. Carroll, R. Parsons, J.C. Rathmell, C.B. Thompson, M.A. Burchill, M.A. Farrar, and L.A. Turka. 2004. Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol 172:5287–5296.PubMedGoogle Scholar
  37. 37.
    Walsh, P.T., J.L. Buckler, J. Zhang, A.E. Gelman, N.M. Dalton, D.K. Taylor, S.J. Bensinger, W.W. Hancock, and L.A. Turka. 2006. PTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs. J Clin Invest 116:2521–2531.PubMedGoogle Scholar
  38. 38.
    Battaglia, M., A. Stabilini, B. Migliavacca, J. Horejs-Hoeck, T. Kaupper, and M.G. Roncarolo. 2006. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol 177:8338–8347.PubMedGoogle Scholar
  39. 39.
    Battaglia, M., A. Stabilini, and M.G. Roncarolo. 2005. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105:4743–4748.PubMedCrossRefGoogle Scholar
  40. 40.
    Strauss, L., T.L. Whiteside, A. Knights, C. Bergmann, A. Knuth, and A. Zippelius. 2007. Selective survival of naturally occurring human CD4+CD25+Foxp3+ regulatory T cells cultured with rapamycin. J Immunol 178:320–329.PubMedGoogle Scholar
  41. 41.
    D'Cruz, L.M., and L. Klein. 2005. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol 6:1152–1159.PubMedCrossRefGoogle Scholar
  42. 42.
    Bayer, A.L., A. Yu, D. Adeegbe, and T.R. Malek. 2005. Essential role for interleukin-2 for CD4+CD25+ T regulatory cell development during the neonatal period. J Exp Med 201: 769–777.PubMedCrossRefGoogle Scholar
  43. 43.
    Setoguchi, R., S. Hori, T. Takahashi, and S. Sakaguchi. 2005. Homeostatic maintenance of natural Foxp3+ CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 201:723–735.PubMedCrossRefGoogle Scholar
  44. 44.
    Murakami, M., A. Sakamoto, J. Bender, J. Kappler, and P. Marrack. 2002. CD25+CD4+ T cells contribute to the control of memory CD8+ T cells. Proc Natl Acad Sci USA 99: 8832–8837.PubMedCrossRefGoogle Scholar
  45. 45.
    Cozzo, C., J. Larkin, 3rd, and A.J. Caton. 2003. Cutting edge: self-peptides drive the peripheral expansion of CD4+CD25+ regulatory T cells. J Immunol 171:5678–5682.PubMedGoogle Scholar
  46. 46.
    Guiducci, C., B. Valzasina, H. Dislich, and M.P. Colombo. 2005. CD40/CD40L interaction regulates CD4+CD25+ Treg homeostasis through dendritic cell-produced IL-2. Eur J Immunol 35:557–567.PubMedCrossRefGoogle Scholar
  47. 47.
    Sempowski, G.D., S.J. Cross, C.S. Heinly, R.M. Scearce, and B.F. Haynes. 2004. CD7 and CD28 are required for murine CD4+CD25+ regulatory T cell homeostasis and prevention of thyroiditis. J Immunol 172:787–794.PubMedGoogle Scholar
  48. 48.
    Tang, Q., K.J. Henriksen, E.K. Boden, A.J. Tooley, J. Ye, S.K. Subudhi, X.X. Zheng, T.B. Strom, and J.A. Bluestone. 2003. Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J Immunol 171:3348–3352.PubMedGoogle Scholar
  49. 49.
    Yamazaki, S., T. Iyoda, K. Tarbell, K. Olson, K. Velinzon, K. Inaba, and R.M. Steinman. 2003. Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J Exp Med 198:235–247.PubMedCrossRefGoogle Scholar
  50. 50.
    Zheng, G., B. Wang, and A. Chen. 2004. The 4-1BB costimulation augments the proliferation of CD4+CD25+ regulatory T cells. J Immunol 173:2428–2434.PubMedGoogle Scholar
  51. 51.
    Thornton, A.M., C.A. Piccirillo, and E.M. Shevach. 2004. Activation requirements for the induction of CD4+CD25+ T cell suppressor function. Eur J Immunol 34:366–376.PubMedCrossRefGoogle Scholar
  52. 52.
    de la Rosa, M., S. Rutz, H. Dorninger, and A. Scheffold. 2004. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur J Immunol 34:2480–2488.PubMedCrossRefGoogle Scholar
  53. 53.
    Thornton, A.M., E.E. Donovan, C.A. Piccirillo, and E.M. Shevach. 2004. Cutting Edge: IL-2 Is Critically Required for the In Vitro Activation of CD4+CD25+ T Cell Suppressor Function. J Immunol 172:6519–6523.PubMedGoogle Scholar
  54. 54.
    Min, B., R. McHugh, G.D. Sempowski, C. Mackall, G. Foucras, and W.E. Paul. 2003. Neonates support lymphopenia-induced proliferation. Immunity 18:131–140.PubMedCrossRefGoogle Scholar
  55. 55.
    Schneider, R., R.K. Lees, T. Pedrazzini, R.M. Zinkernagel, H. Hengartner, and H.R. MacDonald. 1989. Postnatal disappearance of self-reactive (Vβ6+) cells from the thymus of Mlsa mice. Implications for T cell development and autoimmunity. J Exp Med 169: 2149–2158.PubMedCrossRefGoogle Scholar
  56. 56.
    Tarbell, K.V., L. Petit, X. Zuo, P. Toy, X. Luo, A. Mqadmi, H. Yang, M. Suthanthiran, S. Mojsov, and R.M. Steinman. 2007. Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med 204:191–201.PubMedCrossRefGoogle Scholar
  57. 57.
    Tarbell, K.V., S. Yamazaki, K. Olson, P. Toy, and R. Steinman. 2004. CD25+CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 199:1467–1477.PubMedCrossRefGoogle Scholar
  58. 58.
    Yamazaki, S., K. Inaba, K.V. Tarbell, and R.M. Steinman. 2006. Dendritic cells expand antigen-specific Foxp3+ CD25+ CD4+ regulatory T cells including suppressors of alloreactivity. Immunol Rev 212:314–329.PubMedCrossRefGoogle Scholar
  59. 59.
    Yamazaki, S., M. Patel, A. Harper, A. Bonito, H. Fukuyama, M. Pack, K.V. Tarbell, M. Talmor, J.V. Ravetch, K. Inaba, and R.M. Steinman. 2006. Effective expansion of alloantigen-specific Foxp3+ CD25+ CD4+ regulatory T cells by dendritic cells during the mixed leukocyte reaction. Proc Natl Acad Sci U S A 103:2758–2763.PubMedCrossRefGoogle Scholar
  60. 60.
    Granucci, F., S. Feau, V. Angeli, F. Trottein, and P. Ricciardi-Castagnoli. 2003. Early IL-2 production by mouse dendritic cells is the result of microbial-induced priming. J Immunol 170:5075–5081.PubMedGoogle Scholar
  61. 61.
    Granucci, F., C. Vizzardelli, N. Pavelka, S. Feau, M. Persico, E. Virzi, M. Rescigno, G. Moro, and P. Ricciardi-Castagnoli. 2001. Inducible IL-2 production by dendritic cells revealed by global gene expression analysis. Nat Immunol 2:882–888.PubMedCrossRefGoogle Scholar
  62. 62.
    Almeida, A.R., B. Zaragoza, and A.A. Freitas. 2006. Indexation as a novel mechanism of lymphocyte homeostasis: the number of CD4+CD25+ regulatory T cells is indexed to the number of IL-2-producing cells. J Immunol 177:192–200.PubMedGoogle Scholar
  63. 63.
    Yu, A., and T.R. Malek. 2006. Selective availability of IL-2 is a major determinant controlling the production of CD4+CD25+Foxp3+ T regulatory cells. J Immunol 177:5115–5121.PubMedGoogle Scholar
  64. 64.
    Gong, D., and T.R. Malek. 2007. Cytokine-dependent Blimp-1 expression in activated T cells inhibits IL-2 production. J Immunol 178:242–252.PubMedGoogle Scholar
  65. 65.
    Villarino, A.V., C.M. Tato, J.S. Stumhofer, Z. Yao, Y.K. Cui, L. Hennighausen, J. O'Shea J, and C.A. Hunter. 2007. Helper T cell IL-2 production is limited by negative feedback and STAT-dependent cytokine signals. J Exp Med 204:65–71.PubMedCrossRefGoogle Scholar
  66. 66.
    Shapiro-Shelef, M., K.I. Lin, L.J. McHeyzer-Williams, J. Liao, M.G. McHeyzer-Williams, and K. Calame. 2003. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19:607–620.PubMedCrossRefGoogle Scholar
  67. 67.
    Turner, C.A. Jr., D.H. Mack, and M.M. Davis. 1994. Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell 77:297–306.PubMedCrossRefGoogle Scholar
  68. 68.
    Kallies, A., E.D. Hawkins, G.T. Belz, D. Metcalf, M. Hommel, L.M. Corcoran, P.D. Hodgkin, and S.L. Nutt. 2006. Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance. Nat Immunol 7:466–474.PubMedCrossRefGoogle Scholar
  69. 69.
    Martins, G.A., L. Cimmino, M. Shapiro-Shelef, M. Szabolcs, A. Herron, E. Magnusdottir, and K. Calame. 2006. Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat Immunol 7:457–465.PubMedCrossRefGoogle Scholar
  70. 70.
    Noguchi, M., H. Yi, H.M. Rosenblatt, A.H. Filipovich, S. Adelstein, W.S. Modi, O.W. McBride, and W.J. Leonard. 1993. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73:147–157.PubMedCrossRefGoogle Scholar
  71. 71.
    Nosaka, T., J.M. van Deursen, R.A. Tripp, W.E. Thierfelder, B.A. Witthuhn, A.P. McMickle, P.C. Doherty, G.C. Grosveld, and J.N. Ihle. 1995. Defective lymphoid development in mice lacking Jak3. Science 270:800–802.PubMedCrossRefGoogle Scholar
  72. 72.
    Russell, S.M., N. Tayebi, H. Nakajima, M.C. Riedy, J.L. Roberts, M.J. Aman, T.S. Migone, M. Noguchi, M.L. Markert, R.H. Buckley, J.J. O'Shea, and W.J. Leonard. 1995. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 270:797–800.PubMedCrossRefGoogle Scholar
  73. 73.
    Thomis, D.C., C.B. Gurniak, E. Tivol, A.H. Sharpe, and L.J. Berg. 1995. Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 270:794–797.PubMedCrossRefGoogle Scholar
  74. 74.
    Cao, X., E.W. Shores, J. Hu-Li, M.R. Anver, B.L. Kelsall, S.M. Russell, J. Drago, M. Noguchi, A. Grinberg, E.T. Bloom et al. 1995. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity 2:223–238.PubMedCrossRefGoogle Scholar
  75. 75.
    Peffault de Latour, R., H.C. Dujardin, F. Mishellany, O. Burlen-Defranoux, J. Zuber, R. Marques, J. Di Santo, A. Cumano, P. Vieira, and A. Bandeira. 2006. Ontogeny, function, and peripheral homeostasis of regulatory T cells in the absence of interleukin-7. Blood 108:2300–2306.PubMedCrossRefGoogle Scholar
  76. 76.
    Kennedy, M.K., M. Glaccum, S.N. Brown, E.A. Butz, J.L. Viney, M. Embers, N. Matsuki, K. Charrier, L. Sedger, C.R. Willis, K. Brasel, P.J. Morrissey, K. Stocking, J.C. Schuh, S. Joyce, and J.J. Peschon. 2000. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med 191:771–780.PubMedCrossRefGoogle Scholar
  77. 77.
    Lodolce, J.P., D.L. Boone, S. Chai, R.E. Swain, T. Dassopoulos, S. Trettin, and A. Ma. 1998. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9:669–676.PubMedCrossRefGoogle Scholar
  78. 78.
    Liu, Y.J., V. Soumelis, N. Watanabe, T. Ito, Y.H. Wang, R.D. Malefyt, M. Omori, B. Zhou, and S.F. Ziegler. 2006. TSLP: an Epithelial Cell Cytokine that Regulates T Cell Differentiation by Conditioning Dendritic Cell Maturation. Annu Rev Immunol 25:193–219.Google Scholar
  79. 79.
    Ziegler, S.F., and Y.J. Liu. 2006. Thymic stromal lymphopoietin in normal and pathogenic T cell development and function. Nat Immunol 7:709–714.PubMedCrossRefGoogle Scholar
  80. 80.
    Watanabe, N., Y.H. Wang, H.K. Lee, T. Ito, Y.H. Wang, W. Cao, and Y.J. Liu. 2005. Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436:1181–1185.PubMedCrossRefGoogle Scholar
  81. 81.
    Chen, W., W. Jin, N. Hardegen, K.J. Lei, L. Li, N. Marinos, G. McGrady, and S.M. Wahl. 2003. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198:1875–1886.PubMedCrossRefGoogle Scholar
  82. 82.
    Fu, S., N. Zhang, A.C. Yopp, D. Chen, M. Mao, D. Chen, H. Zhang, Y. Ding, and J.S. Bromberg. 2004. TGF-beta induces Foxp3 + T-regulatory cells from CD4 + CD25 – precursors. Am J Transplant 4:1614–1627.PubMedCrossRefGoogle Scholar
  83. 83.
    Marie, J.C., J.J. Letterio, M. Gavin, and A.Y. Rudensky. 2005. TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med 201: 1061–1067.PubMedCrossRefGoogle Scholar
  84. 84.
    Schramm, C., S. Huber, M. Protschka, P. Czochra, J. Burg, E. Schmitt, A.W. Lohse, P.R. Galle, and M. Blessing. 2004. TGFbeta regulates the CD4+CD25+ T-cell pool and the expression of Foxp3 in vivo. Int Immunol 16:1241–1249.PubMedCrossRefGoogle Scholar
  85. 85.
    Gorelik, L., and R.A. Flavell. 2002. Transforming growth factor-beta in T-cell biology. Nat Rev Immunol 2:46–53.PubMedCrossRefGoogle Scholar
  86. 86.
    Letterio, J.J. 2005. TGF-beta signaling in T cells: roles in lymphoid and epithelial neoplasia. Oncogene 24:5701–5712.PubMedCrossRefGoogle Scholar
  87. 87.
    Watkins, S.J., L. Jonker, and H.M. Arthur. 2006. A direct interaction between TGFbeta activated kinase 1 and the TGFbeta type II receptor: implications for TGFbeta signalling and cardiac hypertrophy. Cardiovasc Res 69:432–439.PubMedCrossRefGoogle Scholar
  88. 88.
    Yu, L., M.C. Hebert, and Y.E. Zhang. 2002. TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. Embo J 21:3749–3759.PubMedCrossRefGoogle Scholar
  89. 89.
    Sato, S., H. Sanjo, T. Tsujimura, J. Ninomiya-Tsuji, M. Yamamoto, T. Kawai, O. Takeuchi, and S. Akira. 2006. TAK1 is indispensable for development of T cells and prevention of colitis by the generation of regulatory T cells. Int Immunol 18:1405–1411.PubMedCrossRefGoogle Scholar
  90. 90.
    Liu, H.H., M. Xie, M.D. Schneider, and Z.J. Chen. 2006. Essential role of TAK1 in thymocyte development and activation. Proc Natl Acad Sci USA 103:11677–11682.PubMedCrossRefGoogle Scholar
  91. 91.
    Wan, Y.Y., H. Chi, M. Xie, M.D. Schneider, and R.A. Flavell. 2006. The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function. Nat Immunol 7:851–858.PubMedCrossRefGoogle Scholar
  92. 92.
    Sakurai, H., P. Singhirunnusorn, E. Shimotabira, A. Chino, S. Suzuki, K. Koizumi, and I. Saiki. 2005. TAK1-mediated transcriptional activation of CD28-responsive element and AP-1-binding site within the IL-2 promoter in Jurkat T cells. FEBS Lett 579:6641–6646.PubMedCrossRefGoogle Scholar
  93. 93.
    Tang, Q., and J.A. Bluestone. 2006. Regulatory T-cell physiology and application to treat autoimmunity. Immunol Rev 212:217–237.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Allison L. Bayer
  • Thomas R. Malek
    • 1
  1. 1.Department of Microbiology and ImmunologyDiabetes Research Institute, Miller School of Medicine, University of MiamiMiamiUSA

Personalised recommendations