A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis.
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.
Nocentini
G
G
Department of Clinical Medicine, Pathology and Pharmacology, University of Perugia, Medical School, Via del Giochetto, 06100 Perugia, Italy.
Giunchi
L
L
Ronchetti
S
S
Krausz
L T
LT
Bartoli
A
A
Moraca
R
R
Migliorati
G
G
Riccardi
C
C
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002999:Clone Cells; D003001:Cloning, Molecular; D003907:Dexamethasone / Q000494:pharmacology; D015723:Gene Library; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006825:Hybridomas; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D021382:Protein Sorting Signals / Q000737:chemistry; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000737:chemistry* / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000737:chemistry* / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D013950:Thymus Gland / Q000276:immunology; D014158:Transcription, Genetic; D014162:Transfection; D014466:Ultraviolet Rays
D053450:Glucocorticoid-Induced TNFR-Related Protein; D021382:Protein Sorting Signals; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C106544:Tnfrsf18 protein, mouse; D003907:Dexamethasone