Early kinetic window of target T cell susceptibility to CD25+ regulatory T cell activity

J Immunol. 2005 Dec 1;175(11):7274-80. doi: 10.4049/jimmunol.175.11.7274.


Peripheral tolerance is maintained in part by thymically derived CD25+CD4+ T cells (regulatory T cells (Tregs)). Their mechanism of action has not been well characterized. Therefore, to get a better understanding of Treg action, we investigated the kinetics of murine Treg activity in vitro. Tregs were suppressive within a surprisingly narrow kinetic window: necessary and sufficient only in the first 6-10 h of culture. Visualization of this time frame, using a sensitive single-cell assay for IL-2, revealed the early elaboration of target cell IL-2 producers in the first 6 h despite the presence of CD25+CD4+ Tregs. However, after 6 h, a rapid rise in the number of IL-2 producers in the absence of Tregs was dramatically abrogated by the presence of Tregs. Importantly, the timing of suppression was dictated by the kinetics of target T cell activation suggesting that early target T cell signals may alter susceptibility to suppression. Modulating target T cell activation signals with provision of CD28, IL-2, or high Ag dose all abrogated suppression of proliferation late in culture. However, only CD28 signals enabled target T cells to resist the early Treg-induced down-regulation of IL-2. Therefore the quality of early target T cell activation signals, in particular engagement of CD28, represents an important control point in the balance between vulnerability and resistance to Treg suppression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD28 Antigens / immunology
  • Cell Proliferation
  • Cells, Cultured
  • Female
  • Immune Tolerance / immunology*
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / immunology
  • Lymphocyte Activation / immunology*
  • Mice
  • Receptors, Interleukin-2 / immunology
  • T-Lymphocytes / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • Time Factors


  • CD28 Antigens
  • Interleukin-2
  • Receptors, Interleukin-2