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 and differentiation of naive CD4(+) T cells into Th2 effector cells. To study the function of GATA-3 during T cell-mediated immune responses in vivo, we investigated CD2-GATA3-transgenic mice in which GATA-3 expression is driven by the CD2 locus control region. Both in the CD4(+) and the CD8(+) T cell population the proportion of cells exhibiting a CD44(high)CD45RB(low)CD62L(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 cell 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 IL-10, reminiscent of Th2 memory cells. In contrast to wild-type CD4(+) cells, which lost GATA-3 expression when cultured under Th1-polarizing conditions, CD2-GATA3-transgenic CD4(+) cells maintained expression of GATA-3 protein. Under Th1 conditions, cellular proliferation of CD2-GATA3-transgenic CD4(+) cells was severely hampered, IFN-gamma production was decreased and Th2 cytokine production was increased. Enforced GATA-3 expression inhibited Th1-mediated in vivo responses, such as Ag-specific IgG2a production or a delayed-type hypersensitivity response to keyhole limpet hemocyanin. Collectively, these observations indicate that enforced GATA-3 expression selectively inhibits Th1 differentiation and induces Th2 differentiation. The increased functional capacity to secrete Th2 cytokines, along with the increased expression of surface markers for Ag-experienced Th2-committed cells, would argue for a role of GATA-3 in Th2 memory formation.
|Keywords||*Membrane Proteins, *Protein Biosynthesis, Animals, Antigens, CD2/genetics, Cell Differentiation/genetics/immunology, Cell Polarity/genetics/immunology, Cells, Cultured, Cytokines/biosynthesis/secretion, DNA-Binding Proteins/*biosynthesis/*genetics/physiology, Down-Regulation/genetics/immunology, Epitopes, T-Lymphocyte/biosynthesis, GATA3 Transcription Factor, Growth Inhibitors/*biosynthesis/*genetics, Immunoglobulin Class Switching/genetics, Immunoglobulin G/biosynthesis, Locus Control Region/immunology, Lymph Nodes/cytology, Lymphocyte Activation/genetics, Lymphocyte Count, Lymphoma, T-Cell/genetics/immunology, Mice, Mice, Transgenic, Research Support, Non-U.S. Gov't, Spleen/cytology, T-Lymphocyte Subsets/cytology/immunology/secretion, Th1 Cells/*cytology, Th2 Cells/*cytology/immunology/*metabolism/secretion, Thymus Gland/cytology, Thymus Neoplasms/genetics/immunology, Trans-Activators/*biosynthesis/*genetics/physiology|
Nawijn, M.C., Dingjan, G.M., Ferreira, R., Lambrecht, B.N.M., Karis, A., Savelkoul, H.F.J., … Grosveld, F.G.. (2001). 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. Journal of Immunology. Retrieved from http://hdl.handle.net/1765/9674