Independent and Epigenetic Regulation of the Interleukin-4 Alleles in CD4 ⁺ T Cells

Abstract

How an individual effector T cell acquires a particular cytokine expression pattern from many possible patterns remains unclear. CD4+ T cells from F1 mice, which allowed assignment of the parental origin of interleukin-4 (IL-4) transcripts, were divided into clones that expressed IL-4 biallelically or monoallelically from either allele. The allelic pattern was transmitted as a stable epigenetic trait. Regulation of cytokine expression by a mechanism that treats each allele independently suggests a probabilistic process by which a diverse repertoire of combinatorially assorted cytokine gene expression patterns could be generated among the clonally related daughters of a single precursor cell.

Analysis of allelic expression patterns of IL‐2, IL‐3, IL‐4, and IL‐13 in human CD4+ T cell clones

“…This has been demonstrated in cell lines derived from IL-4/huCD2-transgenic mice, in which certain clones showed allele expression ratios as low as 4:1 [9]. The data supporting the existence of a population of cells showing stable expression of one allele of the murine IL-4 gene are strong [7][8][9]. The pattern of unbalanced expression of IL-4 alleles seen here may indicate that the expression of the IL-4 gene is not sufficiently tightly regulated in the cells studied to ensure complete silencing of one allele in certain clones, resembling the phenomenon seen in IL-4/huCD2-transgenic mice.…”

“…The murine IL-4 gene was also one of the earliest reported as displaying monoallelic expression [8,9]. On examination of human IL-4 gene expression (Table 1), we found IL-4 expression predominantly in Th2 clones, with a few Th1 clones showing very low levels of expression.…”

“…Previous reports on the allelic expression of cytokine genes have analyzed mouse T cell clones, single T cells, knock-in or knock-out mice [5,[7][8][9][10][11], with one report describing the monoallelic expression of the IL-2 gene in single human T cells [6]. This is the first broad examination of allelic expression patterns of cytokine genes in human T cell clones.…”

Hypermethylation of Ron proximal promoter associates with lack of full-length Ron and transcription of oncogenic short-Ron from an internal promoter

“…We suggest at least two possibilities to explain these observations: hypermethylation of the proximal promoter (1) might lead to chromatin modifications enabling the activation of a downstream, intragenic promoter from which sfRon is transcribed; or (2) it could activate the intragenic promoter by default, owing to the higher availability of transcription factors (TF) common to both promoter regions, as expected in promotercompetition models (Bix and Locksley, 1998;Saleh et al, 2004). The presence of predicted TF-binding sites common to both the proximal (CpG-type) and the internal (TATA-type) promoters is therefore indicative and, if verified experimentally, would support such model.…”

Association between IL-4 genotype and IL-4 production in the Japanese population

“…[2][3][4][5] During the differentiation of mouse naive CD4 + T cells, IL-4 plays a necessary early role in the generation of IL-4 producing effector cells in vitro and in vivo: IL-4 is required for the subsequent appearance of IL-4-producing cells, and thus for Th2 lineage commitment. [6][7][8] Furthermore Bix et al 9 documented that IL-4 gene allelic expression was regulated in a probabilistic manner and indicated the possibility that microenvironmental signals such as IL-12 or IL-4 could influence the prevalence of cells that express distinct cytokine patterns.…”