Efficient expansion of regulatory T cells in vitro and in vivo with a CD28 superagonist

Eur J Immunol. 2003 Mar;33(3):626-38. doi: 10.1002/eji.200323570.


CD4(+)CD25(+) T cells play a central role in the suppression of autoimmunity and inflammation, making their in vivo expansion a highly attractive therapeutic target. By phenotyping with a novel rat CTL antigen-4 (CTLA-4)-specific monoclonal antibody (mAb) and functional in vitro assays, we here first establish that rat CD4(+)CD25(+) T cells correspond to the regulatory T cells (Treg cells) described in mice and humans: they constitutively express CTLA-4, produce IL-10 but not IL-2, and are able to suppress the proliferation of costimulated CD25-negative indicator cells. Furthermore, we show that rat Treg cells respond less well than CD25(-) T cells to conventional costimulation, but are readily expanded in vitro with "superagonistic" CD28-specific mAb which are potent mitogens for all T cells without the need for TCR engagement. In vivo, functional Treg cells are preferentially expanded by CD28 stimulation over other T cell subsets, leading to a 20-fold increase within 3 days in response to a single antibody dose. These data suggest that CD28-driven activation of Treg cells may be highly effective in the treatment of inflammatory and autoimmune diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Animals
  • Antigens, CD
  • Antigens, Differentiation / analysis
  • CD28 Antigens / physiology*
  • CD4 Antigens / analysis
  • CTLA-4 Antigen
  • Immunoconjugates*
  • Interleukin-10 / biosynthesis
  • Interleukin-2 / analysis
  • Mice
  • Mice, Inbred BALB C
  • Rats
  • Rats, Inbred Lew
  • Receptors, Interleukin-2 / analysis
  • T-Lymphocytes / immunology*
  • T-Lymphocytes, Regulatory / physiology


  • Antigens, CD
  • Antigens, Differentiation
  • CD28 Antigens
  • CD4 Antigens
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ctla4 protein, mouse
  • Ctla4 protein, rat
  • Immunoconjugates
  • Interleukin-2
  • Receptors, Interleukin-2
  • Interleukin-10
  • Abatacept