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 hybrido ma (3DO) cells by the differential display technique, we have cloned a new gent, GITR (glucocorticoid-induced tumor necrosis factor receptor family-related gene) encoding a ne cv member of the tumor necrosis fa ctor/nerve growth factor receptor family. GITR is a 228-amino acids ty pe I transmembrane protein characterized by three cysteine pseudorepea ts in the extracellular domain and similar to CD27 and 4-1BB in the in tracellular domain. GITR resulted to be expressed in normal T lymphocy tes from thymus, spleen, and lymph nodes, although no expression was d etected in other nonlymphoid tissues, including brain, kidney, and liv er, Furthermore, GITR expression was induced in T lymphocytes upon act ivation by anti-CD3 mAb, Con A, or phorbol 12-myristate 13-acetate plu s Ca-ionophore treatment, The constitutive expression of a transfected GITR gene induced resistance to anti-CD3 mAb-induced apoptosis, where as antisense GITR mRNA expression lead to increased sensitivity, The p rotection toward T cell receptor-induced apoptosis was specific, becau se other apoptotic signals (Fas triggering, dexamethasone treatment, o r 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 dea th.