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Original Article

^a Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Rm. 11N311, 10 Center Dr. – MSC 1892, Bethesda, MD 20892-1892.301-594-3095301-496-5046

Interleukin (IL)-4 and IL-12 together with T cell receptor (TCR) engagement are crucial for the differentiation of CD4⁺ T cells into T helper (Th)2 or Th1 cells, respectively. Although IL-4 receptors (IL-4Rs) but not IL-12Rs are expressed on naive CD4⁺ T cells, IL-4 has no apparent advantage over IL-12 in driving naive T cell differentiation when the cells are primed with both IL-4 and IL-12 in vitro. It was found that IL-4–induced phosphorylation of Janus kinases 1 and 3, IL-4R, signal transducer and activator of transcription 6, and insulin receptor substrate 2 was strikingly but transiently inhibited by TCR ligation both in conventional and TCR transgenic T cells. TCR engagement also blocked the expression of an IL-4–inducible gene. Signals induced by other cytokines, including IL-2, IL-6, and interferon , but not by insulin-like growth factor 1, were also blocked by TCR engagement. The capacity of various inhibitors to reverse TCR-mediated inhibition of IL-4 signaling suggested that activation of the Ras–mitogen-activated protein kinase pathway and of the calcineurin pathway contribute to desensitizing IL-4R. IL-4 responsiveness returned at about the time (12 h) that IL-12–mediated signaling was first observed. Thus, through different mechanisms, neither IL-4R nor IL-12R has any clear advantage in polarizing cells; rather, the availability of cytokine is probably the limiting factor in this process.

Key Words: cytokine signal transduction • T cell activation and differentiation • cross-talk • calcineurin • mitogen-activated protein kinase

Abbreviations used in this paper: c, IL-2R chain; CsA, cyclosporin A; ERK, extracellular signal–regulated kinase; IGF, insulin-like growth factor; IRS, insulin receptor substrate; Jak, Janus kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; NFAT, nuclear factor of activated T cells; PCC, pigeon cytochrome c; PKC, protein kinase C; PTB, phosphotyrosine binding; SOCS, suppressor of cytokine signaling; Stat, signal transducer and activator of transcription.

J. Zhu and H. Huang contributed equally to this work.

H. Huang's present address is the Department of Cell Biology, Loyola University Strich School of Medicine, Maywood, IL 60153.

© 2000 The Rockefeller University Press

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