Biphasic regulation of Il2 transcription in CD4+ T cells: roles for TNF-alpha receptor signaling and chromatin structure.
We describe a novel biphasic regulation of Il2 transcription in naive CD4(+) T cells. Few ( approximately 5%) CD4(+) T cells transcribe Il2 within 6 h of anti-TCR-beta plus anti-CD28 stimulation (early phase). Most naive CD4(+) T cells do not initiate Il2 transcription until after an additional approximately 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.
McKarns
Susan C
SC
Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. mckarnss@health.missouri.edu
Schwartz
Ronald H
RH
D000107:Acetylation; D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D009707:Nucleosomes / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
D015703:Antigens, CD; D018106:CD28 Antigens; D002843:Chromatin; D006657:Histones; D007376:Interleukin-2; D009707:Nucleosomes; D020569:Proto-Oncogene Proteins c-rel; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha