Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells to generate a Th2-inducing cytokine environment.
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.
Yamane
Hidehiro
H
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Zhu
Jinfang
J
Paul
William E
WE
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D003713:Dendritic Cells; D005452:Fluoresceins / Q000378:metabolism; D050990:GATA3 Transcription Factor; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000502:physiology*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D050799:STAT5 Transcription Factor; D013388:Succinimides / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D002070:Butadienes; D016207:Cytokines; D004268:DNA-Binding Proteins; D005452:Fluoresceins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007376:Interleukin-2; D008894:Milk Proteins; D009570:Nitriles; D010455:Peptides; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D013388:Succinimides; D015534:Trans-Activators; C113580:U 0126; D015847:Interleukin-4; D007371:Interferon-gamma; D020930:MAP Kinase Kinase Kinases