Enforced expression of GATA-3 severely reduces human thymic cellularity

Following bone marrow transplantation, patients often suffer from immune in competence by reduced or late T cell development. Moreover, adult bone marr ow stern cells have a lower capacity to generate T cells compared with feta l liver- and umbilical cord blood-derived progenitors. Therefore, enhancing thymic-dependent T cell generation might hold great therapeutic potential. GATA-3 is a transcription factor that is essential in T cell development. In this study we examined the therapeutic potential of GATA-3 to enhance T cell generation by overexpressing GATA-3 in T cell progenitors followed by fetal thymic organ culture (FTOC). We observed that early during FTOC, ther e was an enhanced differentiation toward the double positive stage of T cel l development. From day 10 of FTOC, however, overexpression of GATA-3 induc ed a severe reduction in thymic cellularity, which probably correlates with the absence of a functional TCR-beta chain. We further show that the frequ ency of apoptosis was increased in GATA-3-transduced thymocytes. Despite th e absence of a functional TCR-beta chain, GATA-3 transduced progenitors wer e able to differentiate into CD8 beta (+) double positive thymocytes. This study shows that a strictly regulated expression of GATA-3 is essential for normal T cell development and this puts severe restrictions on the potenti al therapeutic use of continuously overexpressed GATA-3.