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

Abstract

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.