By comparing untreated and dexamethasone-treated murine T cell hybridoma (3DO) cells by the differential display technique, we have cloned a new gene, GITR (glucocorticoid-induced tumor necrosis factor receptor family-related gene) encoding a new member of the tumor necrosis factor/nerve growth factor receptor family. GITR is a 228-amino acids type I transmembrane protein characterized by three cysteine pseudorepeats in the extracellular domain and similar to CD27 and 4-1BB in the intracellular domain. GITR resulted to be expressed in normal T lymphocytes from thymus, spleen, and lymph nodes, although no expression was detected in other nonlymphoid tissues, including brain, kidney, and liver. Furthermore, GITR expression was induced in T lymphocytes upon activation by anti-CD3 mAb, Con A, or phorbol 12-myristate 13-acetate plus Ca-ionophore treatment. The constitutive expression of a transfected GITR gene induced resistance to anti-CD3 mAb-induced apoptosis, whereas antisense GITR mRNA expression lead to increased sensitivity. The protection toward T cell receptor-induced apoptosis was specific, because other apoptotic signals (Fas triggering, dexamethasone treatment, or UV irradiation) were not modulated by GITR transfection. Thus, GITR is a new member of tumor necrosis factor/nerve growth factor receptor family involved in the regulation of T cell receptor-mediated cell death.

GITR (glucocorticoid‐induced TNFR family related gene) is a member of the TNFR superfamily (TNFRSF) that is expressed in different cell types, including T lymphocytes. Because of a high homology in its cytoplasmic region with other known costimulatory members of the TNFRSF, we investigated whether GITR played a costimulatory role in T lymphocyte subpopulations. Our results show that the proliferation response of CD8⁺ and CD4⁺ peripheral T cell subpopulations was potentiated when a GITR costimulus was added to an anti‐CD3 stimulus. Furthermore, expression of the main activation‐induced receptor (IL‐2Rα) and production of IL‐2 and IFN‐γ were increased more with a GITR costimulus than with anti‐CD3 alone. GITR stimulation also enhanced anti‐CD3‐induced ERK phosphorylation, suggesting that GITR is involved in MAPK‐pathway activation. Interestingly, CD4⁺CD25⁺ regulatory T cell (Treg cell) proliferation was triggered by the GITR costimulus; Treg cell proliferation was paralleled by the loss of the anergic phenotype and suppressor activity. Nevertheless, unstimulated GITR^–/– CD4⁺CD25⁺ and GITR^+/+ CD4⁺CD25⁺ cells were equally able to exert suppressor activity on CD4⁺CD25^– responder cells. These results indicate a novel function for GITR as costimulatory molecule of T cell subsets.