GITR ligand-costimulation activates effector and regulatory functions of CD4+ T cells

Biochem Biophys Res Commun. 2008 May 16;369(4):1134-8. doi: 10.1016/j.bbrc.2008.03.024. Epub 2008 Mar 17.


Engagement of glucocorticoid-induced TNFR-related protein (GITR) enables the costimulation of both CD25(-)CD4(+) effector (Teff) and CD25(+)CD4(+) regulatory (Treg) cells; however, the effects of GITR-costimulation on Treg function remain controversial. In this study, we examined the effects of GITR ligand (GITRL) binding on the respective functions of CD4(+) T cells. GITRL-P815 transfectants efficiently augmented anti-CD3-induced proliferation and cytokine production by Teff cells. Proliferation and IL-10 production in Treg were also enhanced by GITRL transfectants when exogenous IL-2 and stronger CD3 stimulation was provided. Concomitant GITRL-costimulation of Teff and Treg converted the anergic state of Treg into a proliferating state, maintaining and augmenting their function. Thus, GITRL-costimulation augments both effector and regulatory functions of CD4(+) T cells. Our results suggest that highly activated and increased ratios of Treg reverse the immune-enhancing effects of GITRL-costimulation in Teff, which may be problematic for therapeutic applications using strong GITR agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Antigen-Presenting Cells / immunology
  • CD3 Complex / metabolism
  • CD4 Antigens / analysis
  • Coculture Techniques
  • Female
  • Interleukin-10 / metabolism
  • Interleukin-2 Receptor alpha Subunit / analysis
  • Ligands
  • Lymphocyte Activation* / drug effects
  • Mice
  • Mice, Inbred BALB C
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*
  • Transfection
  • Tumor Necrosis Factors / agonists*
  • Tumor Necrosis Factors / genetics


  • Antibodies, Monoclonal
  • CD3 Complex
  • CD4 Antigens
  • Interleukin-2 Receptor alpha Subunit
  • Ligands
  • Tnfsf18 protein, mouse
  • Tumor Necrosis Factors
  • Interleukin-10