Analysis of intergenic transcription in the human IL-4/IL-13 gene cluster

During the differentiation of naïve CD4+ precursors to T helper 1 (Th1) or Th2 effector cells, several epigenetic changes occur in a lineage-specific manner at the IFN-gamma or IL-4/IL-13 loci. These changes result in alterations in the chromatin structure of these loci and, hence, lineage-restricted expression of the corresponding cytokines. Intergenic transcripts have recently been shown to regulate the expression of genes in the beta-globin locus; therefore, we have examined the Th2 cytokine gene cluster during human Th1/Th2 differentiation and in a transgenic mouse line containing the human IL-4/IL-13 genes for intergenic transcripts. We show for the first time that intergenic transcription of this locus is restricted to tissues and lineages in which IL-4 and IL-13 are expressed. We also show that intergenic transcription in the IL-4/IL-13 locus is up-regulated after Th2 differentiation. Furthermore, we demonstrate that the Th2 cytokines and intergenic transcripts are detectable in the thymus. We propose that intergenic transcription is tightly associated with transcriptional competence for the Th2 cytokines and may play a role in their regulation. These results support a progressive differentiation model of T cell lineage commitment.