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Biphasic Regulation of Il2 Transcription in CD4⁺ T Cells: Roles for TNF- Receptor Signaling and Chromatin Structure¹

Susan C. McKarns^2,*, and Ronald H. Schwartz^*

^* Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Center for Cellular & Molecular Immunology, Hugh E. Stephenson, Jr. Department of Surgery and Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212

We describe a novel biphasic regulation of Il2 transcription in naive CD4⁺ T cells. Few (5%) CD4⁺ T cells transcribe Il2 within 6 h of anti-TCR-β plus anti-CD28 stimulation (early phase). Most naive CD4⁺ T cells do not initiate Il2 transcription until after an additional 12 h of T cell stimulation (late phase). In comparison, essentially all previously activated (Pre-Ac) CD4⁺ T cells that transcribe Il2 do so with an early-phase response. Late-phase Il2 expression mostly requires c-Rel, CD28, and TNFR signaling. In contrast, early-phase transcription is only partly c-Rel and CD28 dependent and TNFR independent. There was also increased stable DNA accessibility at the Il2 locus and elevated c-Rel expression in resting Pre-Ac CD4⁺ cells. Upon T cell activation, a faster and greater increase in DNA accessibility as well as c-Rel nuclear expression were observed in Pre-Ac CD4⁺ cells relative to naive CD4⁺ T cells. In addition, both acetylated histone H3 and total H3 decreased at the Il2 locus upon rechallenge of Pre-Ac CD4⁺ T cells, whereas increased acetylated histone H3 with no change in total H3 was observed following activation of naive CD4⁺ T cells. We propose a model in which nucleosome disassembly facilitates rapid initiation of Il2 transcription in CD4⁺ T cells, and suggest that a threshold level of c-Rel must be reached for Il2 promoter activity in both naive and Pre-Ac CD4⁺ T cells. This is provided, at least partially, by TNFR signaling during priming, but not during recall.

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 the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Susan C. McKarns, Center for Cellular & Molecular Immunology, Departments of Surgery and Molecular Microbiology and Immunology, University of Missouri-Columbia School of Medicine, M616 Medical Sciences Building, One Hospital Drive, Columbia, MO 65212. E-mail address: mckarnss{at}health.missouri.edu

³ Abbreviations used in this paper: RE, response element; 7-AAD, 7-aminoactinomycin D; ChIP, chromatin immunoprecipitation; CsA, cyclosporin A; Ct, threshold cycle; MFI, mean fluorescence intensity; MNase, micrococcal nuclease; PF, pentoxifylline; Pre-Ac, previously activated; qPCR, quantitative PCR; WT, wild type; KI, Knock in.