Enforced expression of GATA-3 severely reduces human thymic cellularity.
Following bone marrow transplantation, patients often suffer from immune incompetence by reduced or late T cell development. Moreover, adult bone marrow stem cells have a lower capacity to generate T cells compared with fetal 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, there was an enhanced differentiation toward the double positive stage of T cell development. From day 10 of FTOC, however, overexpression of GATA-3 induced a severe reduction in thymic cellularity, which probably correlates with the absence of a functional TCR-beta chain. We further show that the frequency of apoptosis was increased in GATA-3-transduced thymocytes. Despite the absence of a functional TCR-beta chain, GATA-3 transduced progenitors were able to differentiate into CD8beta(+) 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 potential therapeutic use of continuously overexpressed GATA-3.
Taghon
T
T
Department of Clinical Chemistry, Ghent University Hospital, Ghent, Belgium.
De Smedt
M
M
Stolz
F
F
Cnockaert
M
M
Plum
J
J
Leclercq
G
G
D000945:Antigens, Differentiation, T-Lymphocyte; D017209:Apoptosis; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D002454:Cell Differentiation; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D050990:GATA3 Transcription Factor; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D019674:Genes, T-Cell Receptor beta; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology; D006801:Humans; D009924:Organ Culture Techniques; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D015534:Trans-Activators