Enforced expression of GATA-3 during T cell development inhibits maturation of CD8 single-positive cells and induces thymic lymphoma in transgenic mice

The zinc finger transcription factor GATA-3 is of critical importance for e arly T cell development and commitment of Th2 cells. To study the role of G ATA-3 in early T cell development, we analyzed and modified GATA-3 expressi on in vivo. In mice carrying a targeted insertion of a lacZ reporter on one allele, we found that GATA-3 transcription in CD4(+)CD8(+) double-positive thymocytes correlated with the onset of positive selection events, i.e., T CR alpha beta up-regulation and CD69 expression. LacZ expression remained h igh (similar to 80% of cells) during maturation of CD4 single-positive (SP) cells in the thymus, but in developing CD8 SP cells the fraction of lacZ-e xpressing cells decreased to < 20%. We modified this pattern by enforced GA TA-3 expression driven by the CD2 locus control region, which provides tran scription of GATA-3 throughout T cell development. In two independent CD2-G ATA3-transgenic lines, similar to 50% of the mice developed thymic lymphobl astoid tumors that were CD4(+)CD8(+/low) and mostly CD3(+). In tumor-free C D2-GATA3-transgenic mice, the total numbers of CD8 SP cells in the thymus w ere within normal ranges, but their maturation was hampered, as indicated b y increased apoptosis of CD8 SP cells and a selective deficiency of mature CD69(low)HSA(low) CD8 SP cells. In the spleen and lymph nodes, the numbers of CD8(+) T cells were significantly reduced. These findings indicate that GATA-3 supports development of the CD4 lineage and inhibits maturation of C D8 SP cells in the thymus.