Transient regulatory T-cells: a state attained by all activated human T-cells

Clin Immunol. 2007 Apr;123(1):18-29. doi: 10.1016/j.clim.2006.10.014. Epub 2006 Dec 19.


CD4(+)CD25(+)FOXP3(+) regulatory T-cells (T(regs)) form an important arm of the immune system responsible for suppressing untoward immune responses. T(regs) can be thymically derived or peripherally induced, even from CD4(+)CD25(-)FOXP3(-) T-cells. FOXP3 expression and in vitro suppressive activity are considered unique hallmarks of this dedicated and stable lineage of regulatory cells. Here we show that virtually all human CD4(+)CD25(-)FOXP3(-) T-cells and CD8(+)CD25(-)FOXP3(-) T-cells attain a transient FOXP3(+)CD25(+) state during activation. In this state of activation, these cells possess the classic phenotype of T(regs), in that they express similar markers and inhibit in vitro proliferation of autologous CD4(+)CD25(-) T-cells. This state is characterized by suppressed IFN-gamma production and robust TNF-alpha and IL-10 production. Interestingly, the great majority of the activated cells eventually downregulate FOXP3 expression, with a concomitant drop in suppressive ability. Our results show that, in humans, FOXP3 expression and T(reg) functionality are not exclusive features of a stable or unique lineage of T-cells but may also be a transient state attained by almost all T-cells. These results warrant caution in interpreting human studies using FOXP3 and suppressive activity as readouts and suggest that attempts to induce "T(regs)" may paradoxically result in induction of effector T-cells, unless stability is confirmed.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Lineage / immunology
  • Cells, Cultured
  • Flow Cytometry
  • Forkhead Transcription Factors / biosynthesis
  • Forkhead Transcription Factors / immunology
  • Humans
  • Lymphocyte Activation / immunology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism


  • FOXP3 protein, human
  • Forkhead Transcription Factors