Enforced expression of GATA-3 in transgenic mice inhibits Th1 differentiation and induces the formation of a T1/ST2-expressing Th2-committed T cell compartment in vivo

The transcription factor GATA-3 is essential for early T cell development a nd differentiation of naive CD4(+) T cells into Th2 effector calls. To stud y the function of GATA-3 during T cell-mediated immune responses in vivo, w e investigated CD2-GATA3-transgenic mice in which GATA-3 expression is driv en by the CD2 locus control region. Both in the CD4(+) and the CD8(+) T cel l population the proportion of cells exhibiting a CD44(high)CD45RB(low)CD62 L(low) Ag-experienced phenotype was increased. In CD2-GATA3-transgenic mice , large fractions of peripheral CD4(+) T cells expressed the IL-1 receptor family member T1/ST2, indicative of advanced Th2 commitment. Upon in vitro T call stimulation, the ability to produce IL-2 and IFN-gamma was decreased . Moreover, CD4(+) T cells manifested rapid secretion of the Th2 cytokines IL-4, IL-5, and IEL-10, reminiscent of Th2 memory cells. In contrast to wil d-type CD4(+) cells, which lost GATA-3 expression when cultured under Th1-p olarizing conditions, CD2-GATA3-transgenic CD4(+) cells maintained expressi on of GATA-3 protein. Under Th1 conditions, cellular proliferation of CD2-G ATA3-transgenic CD4(+) cells was severely hampered, IFN-gamma production wa s decreased and Th2 cytokine production was increased. Enforced GATA-3 expr ession inhibited Thl-mediated in vivo responses, such as Ag-specific IgG2a production or a delayed-type hypersensitivity response to keyhole limpet he mocyanin. Collectively, these observations indicate that enforced GATA-3 ex pression selectively inhibits Th1 differentiation and induces Th2 different iation. The increased functional capacity to secrete Th2 cytokines, along w ith the increased expression of surface markers for Ag-experienced Th2-comm itted cells, would argue for a role of GATA-3 in Th2 memory formation.