IFN-alpha Regulates IL-21 and IL-21R Expression in Human NK and T Cells

Interleukin (IL)-21 is a T cell-derived cytokine that regulates innate and adaptive immune responses. IL-21 receptor (IL-21R), which is expressed in natural killer (NK) and T cells, is structurally homologous to IL-2Rbeta and IL-15Ralpha. These receptors also share a common cytokine receptor gamma-chain with IL-4, IL-7, and IL-9. Macrophage- or dendritic cell-derived interferon (IFN)-alpha/beta is a key cytokine in regulation of NK and T cell functions. We demonstrate here that in addition to activating IFN-gamma gene expression, IFN-alpha/beta and IL-12 enhance the mRNA expression of IL-21 in activated human T cells. In addition, IFN-alpha/beta enhanced T cell receptor stimulation-induced IL-21 and IFN-gamma gene expression in resting T cells. The promoter analysis of IL-21 gene revealed a putative IFN-gamma activation site element, which was found to bind signal transducer and activator of transcription 1 (STAT1), STAT2, STAT3, and STAT4 proteins in IFN-alpha/beta-stimulated NK or T cell extracts. In contrast to IL-21 expression, IFN-alpha/beta down-regulated IL-21R mRNA expression in NK and T cells. IFN-alpha/beta-induced down-regulation of IL-21R expression resulted in reduced STAT3 phosphorylation and DNA binding after IL-21 stimulation. In conclusion, our results suggest a novel role for IFN-alpha/beta in the regulation of IL-21 response.