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Ikaros Enforces the Costimulatory Requirement for IL2 Gene Expression and Is Required for Anergy Induction in CD4⁺ T Lymphocytes¹

Rajan M. Thomas^*, Neelanjana Chunder^*, Chunxia Chen^*, Sarah E. Umetsu, Susan Winandy and Andrew D. Wells^2,*,

^* Joseph Stokes, Jr. Research Institute, Children’s Hospital of Philadelphia, Philadelphia, PA 19104; Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; and Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104

T cell activation results in dynamic remodeling of the chromatin at the IL2 promoter and induction of IL2 gene transcription. These processes are each dependent upon CD28 costimulation, but the molecular basis for this requirement is not clear. The IL2 promoter contains consensus-binding elements for Ikaros, a lymphocyte-specific zinc-finger DNA-binding protein that can regulate gene expression by recruiting chromatin-remodeling complexes. We find that native Ikaros in CD4⁺ T cells exhibits sequence-specific binding to these elements in vitro, and interacts with the endogenous IL2 promoter in vivo, in a manner dependent upon its DNA-binding domain. This binding has important consequences on the regulation of the IL2 gene, because CD4⁺ T cells with reduced Ikaros DNA-binding activity no longer require signals from the TCR or CD28 for histone acetylation at the endogenous IL2 promoter, and no longer require CD28 costimulation for expression of the IL2 gene. Furthermore, CD4⁺ T cells with reduced Ikaros activity are resistant to clonal anergy induced by TCR ligation in the absence of either CD28 or IL-2R signals. These results establish Ikaros as a transcriptional repressor of the IL2 gene that functions through modulation of chromatin structure and has an obligate role in the induction of anergy.

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 National Institutes of Health Grant (NIH) AI059881 (to A.D.W.), the Joseph Stokes, Jr. Research Institute, the Fred and Suzanne Biesecker Pediatric Liver Center at Children’s Hospital of Philadelphia, and NIH Grant CA104962 (to S.W.).

² Address correspondence and reprint requests to Dr. Andrew D. Wells, 916E Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, PA 19104. E-mail address: adwells{at}mail.med.upenn.edu

³ Abbreviations used in this paper: HAT, histone acetyltransferase; HDAC, histone deacetylase; NURD, nucleosome remodeling and DNA methylation; ChIP, chromatin immunoprecipitation; AcH3, acetylation of histone H3; TCE_d, distal T cell element; NFIL-2B, IL-2 B footprint nuclear binding factor; CtBP; C-terminal-binding protein; Sin, suppressor interacting.