The Journal of Experimental Medicine
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Published online 3 July 2000.
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© The Rockefeller University Press, 0022-1007/2000/7/105/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 1, July 3, 2000 105-116

Original Article

Gata-3 Induces T Helper Cell Type 2 (Th2) Cytokine Expression and Chromatin Remodeling in Committed Th1 Cells

Hyun Jun Leea, Naofumi Takemotob, Hirokazu Kurataa, Yumiko Kamogawab,c, Shoichiro Miyatakeb,c, Anne O'Garraa, and Naoko Araia

a Department of Immunology, DNAX Research Institute, Palo Alto, California 94304-1104
b Department of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-0071, Japan
c Core Research for Evolutionary Science and Technology (CREST), Saitama 332-0012, Japan
DNAX Research Institute of Molecular and Cellular Biology, 901 California Ave., Palo Alto, CA 94304-1104.650-496-1200650-496-1260

arai{at}dnax.org

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 NH2-terminal transactivation domain and the COOH-terminal zinc finger domain of GATA-3 were critical, whereas the NH2-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.

Key Words: CD4 • differentiation • signaling • cytokines • cAMP

Abbreviations used in this paper: EGFP, enhanced green fluorescent protein; HS, DNaseI-hypersensitive.

© 2000 The Rockefeller University Press


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