GATA-3 induces T helper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Th1 cells.
Committed T helper type 1 (Th1) and Th2 effector cells, resulting from chronic antigenic stimulation in interleukin (IL)-12 and IL-4, are implicated in the pathology of autoimmune and allergic diseases. Committed Th1 cells cannot be induced to change their cytokine profiles in response to antigenic stimulation and Th2 cytokine-inducing conditions. Here, we report that ectopic expression of GATA-3 induced Th2-specific cytokine expression not only in developing Th1 cells but also in otherwise irreversibly committed Th1 cells and a Th1 clone, HDK1. Moreover, cAMP, an inhibitor of cytokine production by Th1 cells, markedly augmented Th2 cytokine production in GATA-3-expressing Th1 cells. Ectopic expression of GATA-3 in developing Th1 cells, but not in Th1 clone HDK1, induced endogenous GATA-3, suggesting an autoregulatory mechanism for maintenance of GATA-3 expression in Th2 cells. Structure-function analyses of GATA-3 revealed that the NH(2)-terminal transactivation domain and the COOH-terminal zinc finger domain of GATA-3 were critical, whereas the NH(2)-terminal zinc finger domain was dispensable for the induction of IL-4. Both zinc fingers, however, were required for IL-5 induction. A Th2-specific DNaseI-hypersensitive site of the IL-4 locus was detected in GATA-3-expressing Th1 cells. Thus, GATA-3 can change the phenotype of committed Th1 cells, previously considered to be irreversible.
Lee
H J
HJ
Department of Immunology, DNAX Research Institute, Palo Alto, California 94304-1104, USA.
Takemoto
N
N
Kurata
H
H
Kamogawa
Y
Y
Miyatake
S
S
O'Garra
A
A
Arai
N
N
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D002843:Chromatin / Q000502:physiology*; D016207:Cytokines / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050990:GATA3 Transcription Factor; D005786:Gene Expression Regulation / Q000276:immunology; D005822:Genetic Vectors; D007371:Interferon-gamma / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D015848:Interleukin-5 / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008979:Moloney murine leukemia virus; D011994:Recombinant Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016335:Zinc Fingers
D002843:Chromatin; D016207:Cytokines; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D015848:Interleukin-5; D011994:Recombinant Proteins; D015534:Trans-Activators; D015847:Interleukin-4; D007371:Interferon-gamma