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Ikaros Is a Regulator of Il10 Expression in CD4⁺ T Cells¹

Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611

IL-10 is a regulatory cytokine critical for controlling inflammatory responses. Here we show that Ikaros, a zinc finger DNA-binding protein, plays an important role in the regulation of Il10 in murine CD4⁺ T cells. Upon initial stimulation of the TCR, T cells deficient in Ikaros express significantly lower levels of IL-10 compared with wild-type T cells. In addition, under Th2 skewing conditions, which induce IL-10 production by wild-type T cells, Ikaros null T cells are unable to properly differentiate, producing only low levels of IL-10. Expression of a dominant-negative isoform of Ikaros in wild-type Th2 cells represses IL-10 production but does not significantly alter expression levels of the genes encoding the transcription factors GATA-3 and T-bet. Furthermore, expression of Ikaros in Ikaros null T cells restores expression of the Th2 cytokines IL-10 and IL-4 while reducing production of the Th1 cytokine, IFN-. Coexpression of Ikaros and GATA-3 further increases IL-10 production, showing that these two factors have an additive effect on activating Il10 expression. Finally, we show that Ikaros binds to conserved regulatory regions of the Il10 gene locus in Th2 cells, supporting a direct role for Ikaros in Il10 expression. Thus, we provide evidence for Ikaros as a regulator of Il10 and Ifng gene expression and suggest a role for Ikaros in directing lineage-specific cytokine gene activation and repression.

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 grants from the National Institutes of Health (R01 CA104962-01A1) and the American Heart Association (0950128G) awarded to S.W. S.E.U. was supported by National Institutes of Health Grant F30 ES015971.

² Address correspondence and reprint requests to Dr. Susan Winandy, Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Morton 6-639, Chicago, IL 60611. E-mail address: s-winandy{at}northwestern.edu

³ Abbreviations used in this paper: ChIP, chromatin immunoprecipitation; Treg, regulatory T.