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.
Nawijn
M C
MC
Department of Immunology, Faculty of Medicine, Erasmus University Rotterdam, Dr. Molewaterplein 50, 3000 DR Rotterdam, The Netherlands.
Dingjan
G M
GM
Ferreira
R
R
Lambrecht
B N
BN
Karis
A
A
Grosveld
F
F
Savelkoul
H
H
Hendriks
R W
RW
D000818:Animals; D018801:CD2 Antigens / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis; D050990:GATA3 Transcription Factor; D006131:Growth Inhibitors / Q000096:biosynthesis* / Q000235:genetics*; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis; D000072179:Interleukin-1 Receptor-Like 1 Protein; D019901:Locus Control Region / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D014176:Protein Biosynthesis; D018123:Receptors, Interleukin; D013154:Spleen / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology*; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology; D013953:Thymus Neoplasms / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology
D018801:CD2 Antigens; D016207:Cytokines; D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D006131:Growth Inhibitors; C486189:Il1rl1 protein, mouse; D007074:Immunoglobulin G; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008565:Membrane Proteins; D018123:Receptors, Interleukin; D015534:Trans-Activators