Interleukin-2-dependent mechanisms of tolerance and immunity in vivo

J Immunol. 2006 May 1;176(9):5255-66. doi: 10.4049/jimmunol.176.9.5255.


IL-2 is a critical T cell growth factor in vitro, but predominantly mediates tolerance in vivo. IL-2 is mainly produced by CD4(+) Th cells, but the role of Th cell-derived IL-2 in vivo is controversial. We demonstrate that during immunity to a tumor/self-Ag, the predominant role of Th cell-derived IL-2 was to maintain IL-2Ralpha (CD25) on CD4(+) T regulatory cells (T(reg)), which resulted in their maintenance of the T(reg) cell lineage factor, Forkhead/winged helix transcription factor (Foxp3), and tolerance. However, in the absence of T(reg) cells, Th cell-derived IL-2 maintained effector T cells and caused autoimmunity. IL-2R signaling was indispensable for T(reg) cell homeostasis and efficient suppressor function in vivo, but, surprisingly, was not required for their generation, because IL-2(-/-) and CD25(-/-) mice both contained Foxp3(+) T cells in the periphery. IL-2R signaling was also important for CD8(+) T cell immunity, because CD25(-/-) tumor-reactive CD8(+) T cells failed to affect established tumors. Conversely, IL-2R signaling was not required for Th cell function. Lastly, administration of anti-IL-2 plus exogenous IL-15 to tumor-bearing mice enhanced the adoptive immunotherapy of cancer. Therefore, Th cell-derived IL-2 paradoxically controls both tolerance and immunity to a tumor/self-Ag in vivo.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Antibodies / immunology
  • Antibodies / pharmacology
  • Autoantigens / immunology
  • Cell Proliferation
  • Cells, Cultured
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation
  • Humans
  • Immune Tolerance / immunology*
  • Immunotherapy
  • Interferon-gamma / metabolism
  • Interleukin-2 / deficiency
  • Interleukin-2 / genetics
  • Interleukin-2 / immunology*
  • Interleukin-2 / metabolism
  • Mice
  • Mice, Transgenic
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Neoplasms / therapy
  • Receptors, Interleukin-2 / metabolism
  • Signal Transduction
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Thymus Gland / immunology
  • Thymus Gland / metabolism
  • Xenograft Model Antitumor Assays


  • Antibodies
  • Autoantigens
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2
  • Receptors, Interleukin-2
  • Interferon-gamma