Identification of a new member of the tumor necrosis factor family and itsreceptor, a human ortholog of mouse GITR

The tumor necrosis factor (TNF) and TNF receptor (TNFR) gene superfamilies regulate diverse biological functions,. including cell proliferation, diffe rentiation, and survival [1-3]. We have identified a new TNF-related ligand , designated human GITR ligand (hGITRL), and its human receptor (hGITR), an ortholog of the recently discovered murine glucocorticoid induced TNFR-rel ated (mGITR) protein [4]. The hGITRL gene mapped to chromosome 1q23, near t he gene for the TNF homolog Fas/CD95 ligand [5], The hGITR gene mapped to c hromosome 1p36, near a cluster of five genes encoding TNFR homologs [1,6]. We found hGITRL mRNA in several peripheral tissues, and detected hGITRL pro tein on cultured vascular endothelial cells. The levels of hGITR mRNA in ti ssues were generally low; in peripheral blood T cells, however, antigen rec eptor stimulation led to a substantial induction of hGITR transcripts. Cotr ansfection of hGITRL and hGITR in embryonic kidney 293 cells activated the anti-apoptotic transcription factor NF-kappa B, via a pathway that appeared to involve TNFR associated factor 2 (TRAF2) [7] and NF-kappa B-inducing ki nase (NIK) [8]. Cotransfection of hGITRL and hGITR in Jurkat T leukemia cel ls inhibited antigen-receptor-induced cell death. Thus, hGITRL and hGITR ma y modulate T lymphocyte survival in peripheral tissues.