IFN-α regulates IL-21 and IL-21R expression in human NK and T cells

Abstract

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-2Rβ and IL-15Rα. These receptors also share a common cytokine receptor γ-chain with IL-4, IL-7, and IL-9. Macrophage- or dendritic cell-derived interferon (IFN)-α/β is a key cytokine in regulation of NK and T cell functions. We demonstrate here that in addition to activating IFN-γ gene expression, IFN-α/β and IL-12 enhance the mRNA expression of IL-21 in activated human T cells. In addition, IFN-α/β enhanced T cell receptor stimulation-induced IL-21 and IFN-γ gene expression in resting T cells. The promoter analysis of IL-21 gene revealed a putative IFN-γ activation site element, which was found to bind signal transducer and activator of transcription 1 (STAT1), STAT2, STAT3, and STAT4 proteins in IFN-α/β-stimulated NK or T cell extracts. In contrast to IL-21 expression, IFN-α/β down-regulated IL-21R mRNA expression in NK and T cells. IFN-α/β-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-α/β in the regulation of IL-21 response.