Mechanism of differential regulation of IL-2 in murine Th1 and Th2 T cell subsets. 1. Induction of IL-2 transcription in Th2 cells by up-regulation of transcription factors with the protein synthesis initiation factor 4E.

Abstract

Regulation of IL-2 gene expression in response to receptor-mediated stimuli is known to be mediated primarily by the IL-2 transcriptional enhancer and multiple transcription factors. However, the mechanism that controls the differential expression of the IL-2 gene in both human and murine CD4+ Th cell subsets (Th1-IL-2+ and Th2-IL-2-) is not clearly understood. Differential IL-2 gene expression was assessed in murine Th1 and Th2 subsets by analyzing the expression of a Escherichia coli lacZ reporter gene under control of the human IL-2 enhancer (IL2ZH) transfected in both T cell subsets. Stimulation of transfected T cells with the mitogen Con A, anti-CD3 Ab, or PMA plus ionomycin activated the IL2ZH construct in Th1 but not Th2 cells. However, IL2ZH was activated in stimulated Th2 cells that were co-transfected with a vector that overexpressed the eukaryotic initiation factor 4E (eIF-4E). It has been shown that eIF-4E is rate limiting for protein synthesis and its overexpression leads to increased rates of protein synthesis. Hence, eIF-4E overexpression could have overcome a deficiency in transcriptionally active levels of IL-2 regulatory factors in Th2 cells leading to IL-2 enhancer activation. This possibility was supported by demonstrating that transcriptionally active levels of the critical IL-2 transcription factor, nuclear factor of activated T cells (NF-AT), occurred only in Th2 cells overexpressing eIF-4E but not in normal Th2 cells, thus indicating that the inability of Th2 cells to express IL-2 was associated with inadequate levels of at least one transcription factor, NF-AT. Moreover, these results were confirmed by the observation that eIF-4E overexpression augmented NF-AT binding activity in Th2 cells. These data suggest that concentrations of inducible transcription factors are a major component of the regulatory mechanisms dictating IL-2 expression and may be under translational control in Th1/Th2 T cell subsets.