Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells

Nat Med. 2005 Nov;11(11):1238-43. doi: 10.1038/nm1312. Epub 2005 Oct 16.


CD4(+)CD25(+) regulatory T (T(reg)) cells have a crucial role in maintaining immune tolerance. Mice and humans born lacking T(reg) cells develop severe autoimmune disease, and depletion of T(reg) cells in lymphopenic mice induces autoimmunity. Interleukin (IL)-2 signaling is required for thymic development, peripheral expansion and suppressive activity of T(reg) cells. Animals lacking IL-2 die of autoimmunity, which is prevented by administration of IL-2-responsive T(reg) cells. In light of the emerging evidence that one of the primary physiologic roles of IL-2 is to generate and maintain T(reg) cells, the question arises as to the effects of IL-2 therapy on them. We monitored T(reg) cells during immune reconstitution in individuals with cancer who did or did not receive IL-2 therapy. CD4(+)CD25(hi) cells underwent homeostatic peripheral expansion during immune reconstitution, and in lymphopenic individuals receiving IL-2, the T(reg) cell compartment was markedly increased. Mouse studies showed that IL-2 therapy induced expansion of existent T(reg) cells in normal hosts, and IL-2-induced T(reg) cell expansion was further augmented by lymphopenia. On a per-cell basis, T(reg) cells generated by IL-2 therapy expressed similar levels of FOXP3 and had similar potency for suppression compared to T(reg) cells present in normal hosts. These studies suggest that IL-2 and lymphopenia are primary modulators of CD4(+)CD25(+) T(reg) cell homeostasis.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / immunology
  • Child
  • Female
  • Forkhead Transcription Factors / analysis
  • Homeostasis / immunology
  • Humans
  • Interleukin-2 / administration & dosage
  • Interleukin-2 / immunology
  • Interleukin-2 / therapeutic use*
  • Lymphocyte Transfusion
  • Lymphopenia / chemically induced
  • Lymphopenia / drug therapy*
  • Lymphopenia / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Receptors, Interleukin-2 / immunology*
  • Receptors, Interleukin-2 / metabolism
  • Recombinant Proteins / therapeutic use
  • Sarcoma / complications
  • Sarcoma / drug therapy
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2
  • Receptors, Interleukin-2
  • Recombinant Proteins