Biphasic regulation of Il2 transcription in CD4+ T cells:: Roles for TNF-α receptor signaling and chromatin structure

We describe a novel biphasic regulation of Il2 transcription in naive CD4(+) T cells. Few (similar to 5%) CD4(+) T cells transcribe 112 within 6 h of anti-TCR-beta plus anti-CD28 stimulation (early phase). Most naive CD4(+) T cells do not initiate 112 transcription until after an additional similar to 12 h of T cell stimulation Oate phase). In comparison, essentially all previously activated (Pre-Ac) CD4(+) T cells that transcribe 112 do so with an early-phase response. Late-phase 112 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 112 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 112 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 112 transcription in CD4(+) T cells, and suggest that a threshold level of c-Rel must be reached for 112 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.