Apoptosis of nur77/N10-transgenic thymocytes involves the Fas/Fas ligand pathway

The orphan nuclear receptor Nur77/N10 has recently been demonstrated to be involved in apoptosis of T cell hybridomas. We report here that chronic expression of Nur77/N10 in thymocytes of transgenic mice results in a dramatic reduction of CD4(+)CD8(+) double-positive as well as CD4(+)CD8(-) and CD4(-)CD8(+) single-positive cell populations due to an early onset of apoptosis. CD4(-)CD8(-) double-negative and CD25(+) precursor cells, however, are unaffected. Moreover, nur77/N10-transgenic thymocytes show increased expression of Fas ligand (Fast), while the levels of the Fas receptor (Fas) are not increased. The mouse spontaneous mutant girl (generalized lymphoproliferative disease) carries; a point mutation in the extracellular domain of the Fast gene that abolishes the ability of Fast to bind to Fas. Thymuses from nur77/N10-transgenic mice on a gld/gld background have increased cellularity and an almost normal profile of thymocyte subpopulations. Our results demonstrate that one pathway of apoptosis triggered by Nur77/N10 in double-positive thymocytes occurs through the upregulation of Fast expression resulting in increased signaling through Fas.