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Blimp-1 Induced by IL-4 Plays a Critical Role in Suppressing IL-2 Production in Activated CD4 T Cells¹

Lu Wang^*, Nicholas van Panhuys, Jane Hu-Li, Sohee Kim^*, Graham Le Gros and Booki Min^2,*

^* Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195; Malaghan Institute of Medical Research, Wellington, New Zealand; and Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

Although an inhibitory function of IL-4 in CD4 T cell IL-2 production has long been recognized, a mechanism mediating the inhibition remains unclear. In this study we demonstrate that IL-4 displays a potent suppressive function in IL-2 production of activated CD4 T cells through STAT6. IL-4-induced IL-2 suppression required IL-2 because IL-2 neutralization restored the production of IL-2 even in the presence of IL-4. In vivo, enhanced IL-2 production was found in nematode-infected IL-4- or STAT6-deficient animals, whereas immunization in the presence of IL-4 substantially diminished IL-2 production by Ag-specific CD4 T cells. IL-2 mRNA expression was reduced when T cells were stimulated in the presence of IL-4, whereas IL-2 mRNA decay was unaltered, suggesting that IL-4 mediates the suppression at a transcriptional level. Blimp-1 induced by IL-4 stimulation in activated CD4 T cells was found to be necessary to mediate the IL-2 inhibition as IL-4-mediated IL-2 suppression was less pronounced in activated CD4 T cells deficient in Blimp-1. Taken together, our results demonstrate a potential link with IL-4, Blimp-1, and IL-2 production, suggesting that Blimp-1 may play an important role in controlling IL-2 production in activated T cells and in adaptive T cell immunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by startup funds from the Cleveland Clinic Foundation and in part by a Scientist Development grant from the American Heart Associations (to B.M.).

² Address correspondence and reprint requests to Dr. Booki Min, Department of Immunology, NB30, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail address: minb{at}ccf.org

³ Abbreviations used in this paper: TTP, tristetraprolin; Tg, transgenic; UTR, untranslated region; Treg, regulatory T cell.

⁴ The online version of this article contains supplemental material.