The Journal of Experimental Medicine
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Published 19 September 2005. doi:10.1084/jem.20051304
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 6, 793-804
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ARTICLE

 Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells to generate a Th2-inducing cytokine environment

Hidehiro Yamane, Jinfang Zhu, and William E. Paul

Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

CORRESPONDENCE William E. Paul: wpaul{at}niaid.nih.gov

T cell receptor (TCR) signaling plays an important role in early interleukin (IL)-4 production by naive CD4+ T cells. This "antigen-stimulated" early IL-4 is sufficient for in vitro Th2 differentiation. Here, we provide evidence that early IL-4 production by naive CD4+ T cells stimulated with cognate peptide requires TCR-induced early GATA-3 expression and IL-2 receptor signaling, both of which are controlled by the degree of activation of extracellular signal-regulated kinase (ERK). Stimulation of naive CD4+ T cells from TCR transgenic mice with low concentrations of peptide-induced IL-2–dependent STAT5 phosphorylation, IL-4-independent early GATA-3 expression, and IL-4 production. Neutralization of IL-2 abolished early IL-4 production without affecting early GATA-3 expression. In addition, naive CD4+ T cells from GATA-3 conditional KO mice failed to produce early IL-4 in response to TCR/CD28 stimulation. Stimulation with high concentrations of peptide abrogated early GATA-3 expression and IL-2–dependent STAT5 phosphorylation, and resulted in the failure to produce early IL-4. This high concentration–mediated suppression of early IL-4 production was reversed by blockade of the ERK pathway. A MEK inhibition rescued early GATA-3 expression and responsiveness to IL-2; these cells were now capable of producing early IL-4 and undergoing subsequent Th2 differentiation.

Abbreviations used: AP-1, activated protein-1; CFSE, 5,6-carboxyfluorescein diacetate succinimidyl ester; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase kinase ; MEK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; PFA, paraformaldehyde; pPCC, pigeon cytochrome c peptide.


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