Modulation of Treg cells/T effector function by GITR signaling is context-dependent

Eur J Immunol. 2013 Sep;43(9):2421-9. doi: 10.1002/eji.201343451. Epub 2013 Jul 3.


Treg cells express high levels of the glucocorticoid-induced tumor necrosis factor-related receptor (GITR), while resting conventional T (Tconv) cells express low levels that are increased upon activation. Manipulation of GITR/GITR-Ligand (GITR-L) interactions results in enhancement of immune responses, but it remains unclear whether this enhancement is secondary to costimulation of Tconv cells or to reversal of Treg-cell-mediated suppression. Here, we used a nondepleting Fc-GITR-L and combinations of WT and GITR KO Treg cells and Tconv cells to reexamine the effects of GITR stimulation on each subpopulation in both unmanipulated mice and mice with inflammatory bowel disease. Treatment of mice with Fc-GITR-L resulted in significant expansion of Treg cells and a modest expansion of Tconv cells. When RAG KO mice were reconstituted with Tconv cells alone, GITR-L resulted in Tconv-cell expansion and severe inflammatory bowel disease. The protective effect of Treg cells was lost in the presence of Fc-GITR-L, secondary to death of the Treg cells. When RAG KO mice were reconstituted with Treg cells alone, the transferred cells expanded normally, and Fc-GITR-L treatment resulted in a loss of Foxp3 expression, but the ex-Treg cells did not cause any pathology. The effects of GITR activation are complex and depend on the host environment and the activation state of the Treg cells and T effector cells.

Keywords: Glucocorticoid-induced tumor necrosis factor-related receptor (GITR); Inflammatory bowel disease; T effector cells; Treg cell.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cell Proliferation
  • Forkhead Transcription Factors / biosynthesis
  • Glucocorticoid-Induced TNFR-Related Protein / deficiency
  • Glucocorticoid-Induced TNFR-Related Protein / genetics
  • Glucocorticoid-Induced TNFR-Related Protein / metabolism*
  • Homeodomain Proteins / genetics
  • Inflammatory Bowel Diseases / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Tumor Necrosis Factors / metabolism*


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Glucocorticoid-Induced TNFR-Related Protein
  • Homeodomain Proteins
  • Tnfrsf18 protein, mouse
  • Tnfsf18 protein, mouse
  • Tumor Necrosis Factors
  • RAG-1 protein